Gamma secretase modulators

ABSTRACT

In its many embodiments, the present invention provides a novel class of heterocyclic compounds as modulators of gamma secretase, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the central nervous system using such compounds or pharmaceutical compositions.

REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/941396 filed Jun. 1, 2007.

l FIELD OF THE INVENTION

The present invention relates to certain heterocyclic compounds usefulas gamma secretase modulators (including inhibitors, antagonists and thelike), pharmaceutical compositions containing the compounds, and methodsof treatment using the compounds and compositions to treat variousdiseases including central nervous system disorders such as, forexample, neurodegenerative diseases such as Alzheimer's disease andother diseases relating to the deposition of amyloid protein. They areespecially useful for reducing Amyloid beta (hereinafter referred to asAβ) production which is effective in the treatment of diseases caused byAβ such as, for example, Alzheimers and Down Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a disease characterized by degeneration and lossof neurons and also by the formation of senile plaques andneurofibrillary change. Presently, treatment of Alzheimer's disease islimited to symptomatic therapies with a symptom-improving agentrepresented by an acetylcholinesterase inhibitor, and the basic remedywhich prevents progress of the disease has not been developed. A methodof controlling the cause of onset of pathologic conditions needs to bedeveloped for creation of the basic remedy of Alzheimer's disease.

Aβ protein, which is a metabolite of amyloid precursor protein(hereinafter referred to as APP), is considered to be greatly involvedin degeneration and loss of neurons as well as onset of dementialconditions (for example, see Klein W L, et al Proceeding NationalAcademy of Science USA, Sep. 2, 2003, 100(18), p. 10417-22, suggest amolecular basis for reversible memory loss.

Nitsch R M, and 16 others, Antibodies against β-amyloid slow cognitivedecline in Alzheimer's disease, Neuron, May 22, 2003, 38(4), p. 547-554)suggest that the main components of Aβ protein are Aβ40 consisting of 40amino acids and Aβ42 having two additional amino acids at theC-terminal. The Aβ40 and Aβ42 tend to aggregate (for example, seeJarrell J T et al, The carboxy terminus of the β amyloid protein iscritical for the seeding of amyloid formation: implications for thepathogenesis of Alzheimer's disease, Biochemistry, May 11, 1993, 32(18),p. 4693-4697) and constitute main components of senile plaques (forexample, (Glenner G G, et al, Alzheimer's disease: initial report of thepurification and characterization of a novel cerebrovascular amyloidprotein, Biochemical and Biophysical Research Communications, May 16,1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaquecore protein in Alzheimer disease and Down syndrome, Proceeding NationalAcademy of Science USA, June 1985, 82(12), p. 4245-4249.).

Furthermore, it is known that mutations of APP and presenelin genes,which is observed in familial Alzheimer's disease, increase productionof Aβ40 and Aβ42 (for example, see Gouras G K, et al, IntraneuronalAβ142 accumulation in human brain, American Journal of Pathology,January 2000, 156(1), p. 15-20. Also, see Scheuner D, et al, NatureMedicine, August 1996, 2(8), p. 864-870; and Forman M S, et al,Differential effects of the Swedish mutant amyloid precursor protein onβ-amyloid accumulation and secretion in neurons and nonneuronal cells,Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p.32247-32253.). Therefore, compounds which reduce production of Aβ40 andAβ42 are expected as an agent for controlling progress of Alzheimer'sdisease or for preventing the disease.

These Aβ3s are produced when APP is cleaved by beta secretase andsubsequently clipped by gamma secretase. In consideration of this,creation of inhibitors of γ secretase and β secretase has been attemptedfor the purpose of reducing production of Aβs. Many of these secretaseinhibitors already known are peptides or peptidomimetics such asL-685,458. L-685,458, an aspartyl protease transition stale mimic, is apotent inhibitor of amyloid β-protein precursor y-secretase activity,Biochemistry, Aug. 1, 2000, 39(30), p. 8698-8704).

Also of interest in connection with the present invention are: US2007/0117798 (Eisai, published May 24, 2007); US 2007/0117839 (Eisai,published May 24, 2007); US 2006/0004013 (Eisai, published Jan. 5,2006); WO 2005/110422 (Boehringer Ingelheim, published Nov. 24, 2005);WO 2006/045554 (Cellzone AG, published may 4, 2006); WO 2004/110350(Neurogenetics , published Dec. 23, 2004); WO 2004/071431 (MyriadGenetics, published Aug. 26, 2004); US 2005/0042284 (Myriad Genetics,published Feb. 23, 2005) and WO 2006/001877 (Myriad Genetics, publishedJan. 5, 2006).

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with A$. It is,therefore, an object of this invention to provide compounds useful inthe treatment or prevention or amelioration of such diseases anddisorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofheterocyclic compounds as gamma secretase modulators (includinginhibitors, antagonists and the like), methods of preparing suchcompounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical formulations comprisingone or more such compounds, and methods of treatment, prevention,inhibition or amelioration of one or more diseases associated with theAβ using such compounds or pharmaceutical compositions.

The compounds of this invention (Formula I) can be useful as gammasecretase modulators and can be useful in the treatment and preventionof diseases such as, for example, Alzheimers disease, mild cognitiveimpairment (MCI), Downs Syndrome, Glaucoma (Guo et. al., Proc. Natl.Acad. Sci. USA 104, 13444-13449 (2007)), Cerebral amyloid angiopathy,stroke or dementia (Frangione et al., Amyloid: J. Protein foldingDisord. 8, suppl. 1, 36-42 (2001), Microgliosis and brain inflammation(M P Lamber, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998)), Olfactoryfunction loss (Getchell, et.al. Neurobiology of Aging, 663-673, 24,2003).

In one embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula I:

wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, G, U and V are as defined below.

In one embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula I:

wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, G, U and V are as defined below.

The compounds of Formula I can be useful as gamma secretase modulatorsand can be useful in the treatment and prevention of diseases such as,for example, central nervous system disorders such as Alzheimers diseaseand Downs Syndrome.

This invention also provides compounds of formula I.

This invention also provides pharmaceutically acceptable salts of thecompounds of formula I.

This invention also provides pharmaceutically acceptable esters of thecompounds of formula I.

This invention also provides pharmaceutically solvates of the compoundsof formula I.

This invention also provides compounds of formula I in pure and isolatedform.

This invention also provides compounds of formula I in pure form.

This invention also provides compounds of formula I in isolated form.

This invention also provides compounds 1A to 42A.

This invention also provides compounds 1 to 7 and 9 to 22.

This invention also provides compounds 1 to 7 and 9.

This invention also provides compounds 10 to 22.

This invention also provides pharmaceutical compositions comprising aneffective amount of one or more (e.g., one) compounds of formula I, or apharmaceutically acceptable salt, ester or solvate thereof, and apharmaceutically acceptable carrier.

This invention also provides pharmaceutical compositions comprising aneffective amount of one or more (e.g., one) compounds of formula I, or apharmaceutically acceptable salt, ester or solvate thereof, and aneffective amount of one or more (e.g., one) other pharmaceuticallyactive ingredients (e.g., drugs), and a pharmaceutically acceptablecarrier.

This invention also provides a method for modulating (includinginhibiting, antagonizing and the like) gamma-secretase, comprisingadministering an effective (i.e., therapeutically effective) amount ofone or more compounds of formula I to a patient in need of treatment.

This invention also provides a method for modulating (includinginhibiting, antagonizing and the like) gamma-secretase, comprisingadministering an effective (i.e., therapeutically effective) amount of acompound of formula I to a patient in need of treatment.

This invention also provides a method of treating one or moreneurodegenerative diseases, comprising administering an effective (i.e.,therapeutically effective) amount of one or more compounds of formula Ito a patient in need of treatment.

This invention also provides a method of treating one or moreneurodegenerative diseases, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula I to apatient in need of treatment.

This invention also provides a method of inhibiting the deposition ofamyloid protein (e.g., amyloid beta protein) in, on or aroundneurological tissue (e.g., the brain), comprising administering aneffective (i.e., therapeutically effective) amount of one or morecompounds of formula I to a patient in need of treatment.

This invention also provides a method of inhibiting the deposition ofamyloid protein (e.g., amyloid beta protein) in, on or aroundneurological tissue (e.g., the brain), comprising administering aneffective (i.e., therapeutically effective) amount of a compound offormula I to a patient in need of treatment. This invention alsoprovides a method of treating Alzheimer's disease, comprisingadministering an effective (i.e., therapeutically effective) amount ofone or more compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective (i.e., therapeutically effective)amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective (i.e., therapeutically effective)amount of one or more compounds of formula I, in combination with aneffective (i.e., therapeutically effective) amount of one or morecholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective (i.e., therapeutically effective)amount of one or more compounds of formula I, in combination with aneffective (i.e., therapeutically effective) amount of one or morecompounds selected from the group consisting of Aβ antibody inhibitors,gamma secretase inhibitors and beta secretase inhibitors.

This invention also provides combinations comprising an effective (i.e.,therapeutically effective) amount of one or more compounds of formula I,in combination with an effective (i.e., therapeutically effective)amount of one or more compounds selected from the group consisting ofcholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H -inden-1-one hydrochloride, i.e., donepezil hydrochloride, availableas the Aricept® brand of donepezil hydrochloride), Aβ antibodyinhibitors, gamma secretase inhibitors and beta secretase inhibitors.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective (i.e., therapeutically effective)amount of a compound of formula I, in combination with an effective(i.e., therapeutically effective) amount of one or more (e.g., one)cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-O-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e., donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride), to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective (i.e., therapeutically effective)amount of one or more compounds of formula I to a patient in need oftreatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective (i.e., therapeutically effective)amount of a compound of formula I to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective (i.e., therapeutically effective)amount of one or more compounds of formula I, in combination with aneffective (i.e., therapeutically effective) amount of one or morecholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-O-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective (i.e., therapeutically effective)amount of a compound of formula I, in combination with an effective(i.e., therapeutically effective) amount of one or more (e.g., one)cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

This invention also provides combination therapies for (1) modulatinggamma-secretase, or (2) treating one or more neurodegenerative diseases,or (3) inhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain), or (4)treating Alzheimer's disease. The combination therapies are directed tomethods comprising the administration of an effective amount of one ormore (e.g. one) compounds of formula I and the administration of aneffective amount of one or more (e.g., one) other pharmaceutical activeingredients (e.g., drugs).

This invention also provides a method of treating mild cognitiveimpairment, comprising administering an effective amount of one or more(e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating glaucoma, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating cerebral amyloidangiopathy, comprising administering an effective amount of one or more(e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating stroke, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating dementia, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating microgliosis,comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating brain inflammation,comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating olfactory functionloss, comprising administering an effective amount of one or more (e.g.,one) compounds of formula I to a patient in need of treatment.

This invention also provides pharmaceutical compositions comprising acombination of an effective amount of one or more (e.g., one) compoundsof formula I, in combination with an effective amount of one or morecompounds selected from the group consisting of cholinesteraseinhibitors, Aβ antibody inhibitors, gamma secretase inhibitors and betasecretase inhibitors. The pharmaceutical compositions also comprise apharmaceutically acceptable carrier.

This invention also provides a kit comprising, in separate containers,in a single package, pharmaceutical compositions for use in combination,wherein one container comprises an effective amount of a compound offormula I in a pharmaceutically acceptable carrier, and anothercontainer (i.e., a second container) comprises an effective amount ofanother pharmaceutically active ingredient, the combined quantities ofthe compound of formula I and the other pharmaceutically activeingredient being effective to: (a) treat Alzheimer's disease, or (b)inhibit the deposition of amyloid protein in, on or around neurologicaltissue (e.g., the brain), or (c) treat neurodegenerative diseases, or(d) modulate the activity of gamma-secretase.

This invention also provides a kit comprising, in separate containers,in a single package, pharmaceutical compositions for use in combination,wherein one container comprises an effective amount of a compound offormula I in a pharmaceutically acceptable carrier, and anothercontainer (i.e., a second container) comprises an effective amount ofanother pharmaceutically active ingredient (as described below), thecombined quantities of the compound of formula I and the otherpharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid protein(e.g., amyloid beta protein) in, on or around neurological tissue (e.g.,the brain), or (c) treat neurodegenerative diseases, or (d) modulate theactivity of gamma-secretase.

This invention also provides any one of the methods disclosed above andbelow wherein the compound is selected from the group consisting of thecompounds 1 to 7 and 9 to 22 (see Table 1).

This invention also provides any one of the methods disclosed above andbelow wherein the compound of formula I is selected from the groupconsisting of the compounds 1A to 40A.

This invention also provides any one of the pharmaceutical compositionsdisclosed above and below wherein the compound is selected from thegroup consisting of the compounds 1 to 7 and 9 to 22.

This invention also provides any one of the pharmaceutical compositionsdisclosed above and below wherein the compound is any one of thecompounds 1A to 40A.

Other embodiments of this invention are directed to any one of theembodiments above or below that are directed to formula I, or the use offormula I (e.g. the embodiments directed to methods of treatment,pharmaceutical compositions and kits), wherein the compound is acompound of formula IA instead of formula I. Those skilled in the artwill appreciate that the compounds of formula I and formula IA areisomers of each other.

DETAILED DESCRIPTION

In one embodiment, the present invention discloses compounds which arerepresented by structural Formula I, or a pharmaceutically acceptablesalt, solvate, ester or prodrug thereof, wherein the various moietiesare described below.

For the compounds of formula I and IA, R¹, R², R⁸, R⁷, R⁸, R⁹, R¹⁰, G, Uand V are each independently selected.

Thus, in one embodiment; the present invention discloses compounds whichare represented by structural Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof, wherein:

-   -   either (i) R² and R⁶ are joined together to form a C4-C8        cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8        membered heterocyclenyl moiety, with each of said cycloalkyl or        heterocyclyl moiety being unsubstituted or optionally        independently being substituted with 1-5 substituents which can        be the same or different, each substituent being independently        selected from the group consisting of the moieties shown below;        or (ii) R² and R⁶ are joined together to form a C4-C8        cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8        membered heterocyclenyl moiety, with each of said cycloalkyl or        heterocyclyl moiety being unsubstituted or optionally        independently being substituted with 1-5 substituents which can        be the same or different, each substituent being independently        selected from the group consisting of the moieties shown below;        and R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl,        C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered        heterocyclenyl moiety, with each of said cycloalkyl or        heterocyclyl moiety being unsubstituted or optionally        independently being substituted with 1-5 substituents which can        be the same or different, each substituent being independently        selected from the group consisting of the moieties shown below;        and

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, 0, —C(O)—, andN(R¹⁴);

R¹, R⁵ and R⁷ (when R⁷ is not joined to R⁶) can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-,cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl- and heterocyclylalkyl-, wherein each of said alkyl-,alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- andheterocyclylalkyl- can be unsubstituted or optionally independentlysubstituted with 1-5 substituents which can be the same or different,each substituent being independently selected from the group consistingof the moieties shown below;

or, alternatively, R¹ and R⁸ are taken together to form a bond (i.e.,there is a triple bond between the carbon atom to which R¹ was bonded toand the carbon to which R⁸ was bonded to, i.e., the compound of formulaI is a compound of formula II:

-   -   and R⁵ and R⁷ are as defined above);

R¹⁴ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵);

R⁸ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- beingunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R¹⁰ is selected from the group consisting of a bond, alkyl-, alkenyl-and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocycylylalkvl- and the moieties:

-   -   where X is O, N(R¹⁴) or S;        wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-,        arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,        heteroaryl-, heteroarylalkyl-, heterocyclyl- heterocyclylalkyl-        for R¹⁰ as well as the above-noted moieties for R¹⁰ can be        unsubstituted or optionally independently substituted with 1-3        substituents which can be the same or different, each being        independently selected from the group consisting of the moieties        shown below; and

R⁹ is selected from the group consisting of alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-can beunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow,

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, arylheterocyclyl, R¹⁸-alkyl, R¹⁸-cycloalkyl,R¹⁸-cycloalkylalkyl, R¹⁸-heterocyclyl, R¹⁸-heterocyclylalkyl, R¹⁸-aryl,R¹⁸-arylalkyl, R¹⁸-heteroaryl and R¹⁸-heteroarylalkyl;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl,—NO₂, halo, heteroaryl, HO-alkyoxyalkyl, -CF₃, —CN, alkyl—CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸ moieties on adjacent carbons can be linkedtogether to form:

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl arid alkynyl groups in R¹, R²-R⁶, R⁵, R⁷, R⁸,R⁹, R¹⁰ and R¹⁴ is independent unsubstituted or optionally substitutedby 1 to 5 R²¹ groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl—N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵;

wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R²¹ is independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, -alkyl—C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)²R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

The statement above: “either (i) R² and R⁶ are joined together to form aC4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8membered heterocyclenyl moiety, with each of said cycloalkyl orheterocyclyl moiety being unsubstituted or optionally independentlybeing substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below; or (ii) R² and R⁶ are joinedtogether to form a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 memberedheterocyclyl or 5-8 membered heterocyclenyl moiety, with each of saidcycloalkyl or heterocyclyl moiety being unsubstituted or optionallyindependently being substituted with 1-5 substituents which can be thesame or different, each substituent being independently selected fromthe group consisting of the moieties shown below; and R⁶ and R⁷ arejoined together to form a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8membered heterocyclyl or 5-8 membered heterocyclenyl moiety, with eachof said cycloalkyl or heterocyclyl moiety being unsubstituted oroptionally independently being substituted with 1-5 substituents whichcan be the same or different, each substituent being independentlyselected from the group consisting of the moieties shown below; “meansthat the occurrences of (i) and (ii) are mutually exclusive and thatonly one of (i) and (ii) can be present at any given time.

It should be understood that when R² and R⁶ are joined together to forma C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8membered heterocyclenyl moiety, each of said cycloalkyl, cycloalkenyl,heterocyclyl or heterocyclenyl moiety independently may optionallyadditionally be fused with an aryl or heteroaryl ring, wherein the ringmoiety resulting from the fusion may be unsubstituted or optionallyindependently substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown above.

It should also be understood that when R⁶ and R⁷ are joined together toform a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclylor 5-8 membered heterocyclenyl moiety, each of said cycloalkyl,cycloalkenyl, heterocyclyl or heterocyclenyl moiety independently mayoptionally additionally be fused with an aryl or heteroaryl ring,wherein the ring moiety resulting from the fusion may be unsubstitutedor optionally independently substituted with 1-5 substituents which canbe the same or different, each substituent being independently selectedfrom the group consisting of the moieties shown above.

In another embodiment of this invention, each of the alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R¹, R²-R⁶,R⁵, R⁷, R⁸, R⁹, R¹⁰ and R¹⁴ is independently unsubstituted or optionallysubstituted by 1 to 5 R²¹ groups independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; wherein each of the alkyl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyland alkynyl groups in R²¹ is independently unsubstituted or substitutedby 1 to 5 R²² groups independently selected from the group consisting ofalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halo,—CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶),—SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R₁₅)(R₁₆), —C(═NOR¹⁵)R¹⁶,—P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶,—CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, ═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

Thus, in one embodiment, the present invention discloses compounds whichare represented by structural Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof, wherein:

either:

(i) R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (a) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, (b) said heterocyclylmoiety is optionally substituted with 1-5 independently selected R²¹substituents, and (c) said cycloalkyl, cycloalkenyl, heterocyclyl orheterocyclenyl moiety is optionally fused with an aryl or heteroarylring, and the ring moiety resulting from the fusion is optionallysubstituted with 1-5 independently selected R²¹ substituents; or

(ii)

(a) R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents, and

(b) R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents; and

(c) said R⁶ and R⁷ cycloalkyl, cycloalkenyl, heterocyclyl orheterocyclenyl moiety is optionally fused with an aryl or heteroarylring, and the ring moiety resulting from the fusion is optionallysubstituted with 1-5 independently selected R²¹ substituents; and

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, andN(R¹⁴);

R¹, R⁵ and R⁷ (when R⁷ is not joined to R⁶) are each being independentlyselected from the group consisting of: H, alkyl-, alkenyl- and alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl-, alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- is optionallysubstituted with 1-5 independently selected R²¹ substituents;

or, alternatively, R¹ and R⁸ are taken together to form a bond (i.e.,there is a triple bond between the carbon atom to which R¹ was bonded toand the carbon to which R⁸ was bonded to, i.e., the compound of formulaI is a compound of formula II:

and R⁵ and R⁷ are as defined above);

R⁸ is selected from the group consisting of: H, alkyl-, alkenyl-,alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- being optionallysubstituted with 1-3 independently selected R²¹ substituents;

R⁹ is selected from the group consisting of: alkyl-, alkenyl-, alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said R⁹ substituents is optionally substituted with 1-3independently selected R²¹ substituents;

R¹⁰ is selected from the group consisting of: a bond, alkyl-, alkenyl-,alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclylalkyl- and themoieties:

wherein X is O, N(R¹⁴) or S; and

wherein each of said R¹⁰ moieties (except for the bond) is optionallysubstituted with 1-3 independently selected R²¹ substituents;

R⁹ is selected from the group consisting of: alkyl-, alkenyl-, alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said R⁹ substituents is optionally substituted with 1-3independently selected R²¹ substituents;

R¹⁴ is selected from the group consisting of: H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶), wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substitutents;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consistingof: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-,heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl,heteroarylalkyl-, arylcycloalkyl-, arylheterocyclyl-, (R¹⁸)_(r)-alkyl,(R¹⁸)_(r)-cycloalkyl-, (R¹⁸)_(r)-cycloalkylalkyl-,(R¹⁸)_(r)-heterocyclyl-, (R¹⁸)_(r)-heterocyclylalkyl-, (R¹⁸)_(r)-aryl,(R¹⁸)_(r)-arylalkyl-, (R¹⁸)_(r)-heteroaryl- and(R¹⁸)_(r)-heteroarylalkyl-, wherein each r is independently 1 to 5;

Each R¹⁸ is independently selected from the group consisting of: alkyl,alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂, halo,heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹, —C(O)OH,—C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸ moieties on adjacent carbons can be linkedtogether to form:

R¹⁹ is selected from the group consisting of: alkyl, cycloalkyl, aryl,arylalkyl and heteroarylalkyl;

R²⁰ is selected from the group consisting of: alkyl, cycloalkyl, aryl,halo substituted aryl, arylalkyl-, heteroaryl and heteroarylalkyl-;

Each R²¹ independently selected from the group consisting of: alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, cycloalkenyl,heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl,heteroarylalkyl-, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵;

Wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl-,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl-, heteroaryl,heteroarylalkyl-, alkenyl and alkynyl groups in R²¹ is optionallysubstituted with 1 to 5 R²² groups; and

Each R²² is independently selected from the group consisting of: alkyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halo, —CF₃,—CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶),—SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶,—P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶,—CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, ═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

In another embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula I:

wherein:

R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, with each of said cycloalkyl or heterocyclyl moiety beingunsubstituted or optionally independently being substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, andN(R¹⁴);

R¹, R⁵ and R⁷ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl- and alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R¹⁴ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶);

R⁸ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- beingunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R¹⁰ is selected from the group consisting of a bond, alkyl-, alkenyl-and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocyclylalkyl- and the moieties:

where X is O, N(R¹⁴) or S;

wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- heterocyclylalkyl- for R¹⁰ as well asthe above-noted moieties for R¹⁰ can be unsubstituted or optionallyindependently substituted with 1-3 substituents which can be the same ordifferent, each being independently selected from the group consistingof the moieties shown below; and

R⁹ is selected from the group consisting of alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow,

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, arylheterocyclyl, R¹⁸-alkyl, R¹⁸-cycloalkyl,R¹⁸-cycloalkylalkyl, R¹⁸-heterocyclyl, R¹⁸-heterocyclylalkyl, R¹⁸-aryl,R¹⁸-arylalkyl, R¹⁸-heteroaryl and R¹⁸-heteroarylalkyl;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl,—NO₂, halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸ moieties on adjacent carbons can be linkedtogether to form:

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkenyl cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R¹, R²-R⁶, R⁵, R⁷, R⁸,R⁹, R¹⁰ and R¹⁴ is independently unsubstituted or optionally substitutedby 1 to 5 R²¹ groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and

wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R²¹ is independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

In another embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula I:

wherein:

R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, with each of said cycloalkyl or heterocyclyl moiety beingunsubstituted or optionally independently being substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow; and R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl,C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8 memberedheterocyclenyl moiety, with each of said cycloalkyl or heterocyclylmoiety being unsubstituted or optionally independently being substitutedwith 1-5 substituents which can be the same or different, eachsubstituent being independently selected from the group consisting ofthe moieties shown below;

and

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, andN(R¹⁴);

R¹, R⁵ and R⁷ (when R⁷ is not joined to R⁶) can be the same ordifferent, each being independently selected from the group consistingof H, alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-,cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl- and heterocyclylalkyl-, wherein each of said alkyl-,alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- andheterocyclylalkyl- can be unsubstituted or optionally independentlysubstituted with 1-5 substituents which can be the same or different,each substituent being independently selected from the group consistingof the moieties shown below;

R¹⁴ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶);

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- beingunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R¹⁰ is selected from the group consisting of a bond, alkyl-, alkenyl-and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl-,heterocyclylalkyl- and the moieties:

where X is O, N(R¹⁴) or S;

wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- heterocyclylalkyl- for R¹⁰ as well asthe above-noted moieties for R¹⁰ can be unsubstituted or optionallyindependently substituted with 1-3 substituents which can be the same ordifferent, each being independently selected from the group consistingof the moieties shown below; and

R⁹ is selected from the group consisting of alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, arylheterocyclyl, R¹⁸-alkyl, R¹⁸-cycloalkyl,R¹⁸-cycloalkylalkyl, R¹⁸-heterocyclyl, R¹⁸-heterocyclylalkyl, R¹⁸-aryl,R¹⁸-arylalkyl, R¹⁸-heteroaryl and R¹⁸-heteroarylalkyl;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl,—NO₂, halo, heteroaryl, HO-alkyoxyalkyl, -CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or, alternately, two R¹⁸ moieties on adjacent carbons can be linkedtogether to form:

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R¹, R²-R⁶,R⁵, R⁷, R⁸, R⁹, R¹⁹ and R¹⁴ is independently unsubstituted or optionallysubstituted by 1 to 5 R²¹ groups independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)²R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and

wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R²¹ is independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.

In another embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula I:

wherein:

U is

or N;

G is O or S;

V is selected from the group consisting of a bond, O, —C(O)—, andN(R¹⁹);

R¹, R⁵ and R⁷ can be the same or different, each being independentlyselected from the group consisting of H, alkyl-, alkenyl- and alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow;

R² and R⁶ are joined together to form a C4-C8 cycloalkyl or a 5-8membered heterocyclyl moiety, with each of said cycloalkyl orheterocyclyl moiety being unsubstituted or optionally independentlybeing substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below;

R¹⁴ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶);

R⁸ is selected from the group consisting of H, alkyl, cycloalkyl, aryland heteroaryl, with each of said alkyl, cycloalkyl, aryl and heteroarylbeing unsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups;

R¹⁰ is selected from the group consisting of a bond, aryl, heteroaryl,cycloalkyl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl,heterocyclylalkyl and the moieties:

where X is O, NH or S;

wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl and theabove-noted moieties for R¹⁰ can be unsubstituted or optionallyindependently substituted with 1-3 substituents which can be the same ordifferent, each being independently selected from the group consistingof halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxygroups; and

R⁹ is selected from the group consisting of alkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl andheterocyclylalkyl wherein each of said alkyl, aryl, heteroaryl andheterocyclyl can be unsubstituted or optionally independentlysubstituted with 1-3 substituents which can be the same or different,each substituent being independently selected from the group consistingof halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxygroups.

In another embodiment of this invention R² and R⁶ are joined together toform a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclylor 5-8 membered heterocyclenyl moiety, wherein: (a) said cycloalkylmoiety is optionally substituted with 1-5 independently selected R²¹substituents, (b) said heterocyclyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (c) saidcycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl moiety isoptionally fused with an aryl or heteroaryl ring, and the ring moietyresulting from the fusion is optionally substituted with 1-5independently selected R²¹ substituents.

In another embodiment of this invention R² and R⁶ are joined together toform a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclylor 5-8 membered heterocyclenyl moiety, wherein: (a) said cycloalkylmoiety is optionally substituted with 1-5 independently selected R²¹substituents, (b) said heterocyclyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (c) saidcycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl moiety is fusedwith an aryl or heteroaryl ring, and the ring moiety resulting from thefusion is optionally substituted with 1-5 independently selected R²¹substituents.

In another embodiment of this invention R² and R⁶ are joined together toform a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclylor 5-8 membered heterocyclenyl moiety, wherein: (a) said cycloalkylmoiety is optionally substituted with 1-5 independently selected R²¹substituents, (b) said heterocyclyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (c) saidcycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl moiety is fusedwith an aryl ring, and the ring moiety resulting from the fusion isoptionally substituted with 1-5 independently selected R²¹ substituents.

In another embodiment of this invention R² and R⁶ are joined together toform a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclylor 5-8 membered heterocyclenyl moiety, wherein: (a) said cycloalkylmoiety is optionally substituted with 1-5 independently selected R²¹substituents, (b) said heterocyclyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (c) saidcycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl moiety is fusedwith a phenyl ring, and the ring moiety resulting from the fusion isoptionally substituted with 1-5 independently selected R²¹ substituents.

In another embodiment of this invention:

(a) R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents, and

(b) R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents; and

(c) said R⁶ and R⁷ cycloalkyl, cycloalkenyl, heterocyclyl orheterocyclenyl moiety is fused with an aryl or heteroaryl ring, and thering moiety resulting from the fusion is optionally substituted with 1-5independently selected R²¹ substituents.

In another embodiment of this invention:

(a) R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents, and

(b) R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents; and

(c) said R⁶ and R⁷ cycloalkyl, cycloalkenyl, heterocyclyl orheterocyclenyl moiety is fused with an aryl ring, and the ring moietyresulting from the fusion is optionally substituted with 1-5independently selected R²¹ substituents.

In another embodiment of this invention:

(a) R² and R⁶ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents, and

(b) R⁶ and R⁷ are joined together to form a C4-C8 cycloalkyl, C4-C8cycloalkenyl, 5-8 membered heterocyclyl or 5-8 membered heterocyclenylmoiety, wherein: (1) said cycloalkyl moiety is optionally substitutedwith 1-5 independently selected R²¹ substituents, and (2) saidheterocyclyl moiety is optionally substituted with 1-5 independentlyselected R²¹ substituents; and

(c) said R⁶ and R⁷ cycloalkyl, cycloalkenyl, heterocyclyl orheterocyclenyl moiety is fused with a phenyl ring, and the ring moietyresulting from the fusion is optionally substituted with 1-5independently selected R²¹ substituents.

In another embodiment, V is selected from the group consisting of abond, O, and N(R¹⁴).

In another embodiment of this invention R¹ and R⁸ are taken together toform a bond (i.e., there is a triple bond between the carbon atom towhich R¹ was bonded to and the carbon to which R⁸ was bonded to, i.e.,the compound of formula I is a compound of formula II:

In another embodiment of this invention:

R¹ is selected from the group consisting of: H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents as described for R¹ in formula I; and

R⁸ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,with each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- beingunsubstituted or optionally independently substituted with 1-3substituents, as described for R⁸ in formula I.

Those skilled in the art will appreciate that for the compounds of theinvention:

are isomers

In another embodiment, U is C(R⁵).

In another embodiment U is C(R⁵) and R⁵ is H.

In another embodiment, U is N.

In another embodiment, G is O.

In another embodiment, G is S.

In another embodiment V is a bond.

In another embodiment V is —O—.

In another embodiment V is —N(R¹⁴)—.

In another embodiment V is —C(O)—.

In another embodiment, R¹ is H.

In another embodiment, R¹ is alkyl.

In another embodiment, R¹ is methyl.

In another embodiment, R² and R⁶ are joined together to form acyclopentyl ring.

In another embodiment, R² and R⁶ are joined together to form acyclopentyl ring, which is substituted with 1-3 substituents which canbe the same or different, each being independently selected from thegroup consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂,hydroxy and alkoxy groups.

In another embodiment, R² and R⁶ are joined together to form acyclohexyl ring.

In another embodiment, R² and R⁶ are joined together to form acyclohexyl ring, which is substituted with 1-3 substituents which can bethe same or different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl),—N(alkyl)₂, hydroxy andalkoxy groups.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a piperidinyl ring including the N of U as the nitrogen of saidpiperidinyl ring, which is unsubstituted.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a piperidinyl ring including the N of U as the nitrogen of saidpiperidinyl ring, wherein said piperidinyl ring is substituted with 1-3substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a pyrrolidinyl ring including the N of U as the nitrogen of saidpyrrolidinyl ring, which is unsubstituted.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a pyrrolidinyl ring including the N of U as the nitrogen of saidpyrrolidinyl ring, wherein said pyrrolidinyl ring is substituted with1-3 substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a piperazinyl ring including the N of U as a nitrogen of saidpiperazinyl ring, which is unsubstituted.

In another embodiment, U is N, G is O, and R² and R⁶ are joined togetherto form a piperazinyl ring including the N of U as a nitrogen of saidpiperazinyl ring, wherein said piperazinyl ring is substituted with 1-3substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R² and R⁶ are joined together to form amorpholinyl ring which is unsubstituted.

In another embodiment, R² and R⁶ are joined together to form amorpholinyl ring, which is substituted with 1-3 substituents which canbe the same or different, each being independently selected from thegroup consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl),—N(alkyl)₂,hydroxy and alkoxy groups.

In another embodiment, R² and R⁶ are joined together to form a pyranylring which is unsubstituted.

In another embodiment, R² and R⁶ are joined together to form a pyranylring, which is substituted with 1-3 substituents which can be the sameor different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl),—N(alkyl)₂, hydroxy andalkoxy groups.

In another embodiment, R² and R⁶ are joined together to form apyrrolidinyl ring which is unsubstituted.

In another embodiment, R² and R⁶ are joined together to form apyrrolidinyl ring, which is substituted with 1-3 substituents which canbe the same or different, each being independently selected from thegroup consisting of halo, alkyl, —CN, —NH₂, —NH(alkyl),—N(alkyl)₂,hydroxy and alkoxy groups.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a ring that isfused with an aryl or heteroaryl ring, said resulting fused ringoptionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with an aryl or heteroaryl ring, saidresulting fused ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with an aryl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a cyclopentylring that is fused with a phenyl ring, said resulting fused ringoptionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3halo, such as, wherein the phenyl moiety is substituted with 1 halo,such as wherein the phenyl moiety is substituted with 1-3 F, such aswhen the phenyl moiety is substituted with 1 F).

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a cyclopentylring that is fused with a phenyl ring, wherein said phenyl moiety issubstituted with 1 F.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, wherein saidphenyl moiety is substituted with 1 F.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aring that is fused with an aryl or heteroaryl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with an aryl or heteroaryl ring,said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with an aryl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with a phenyl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with a phenyl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, wherein said phenylmoiety is substituted with 1 F.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, wherein saidphenyl moiety is substituted with 1 F.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents (e.g., wherein the phenyl moiety is substituted with 1-3independently selected halos, such as, wherein the phenyl moiety issubstituted with 1 halo, such as wherein the phenyl moiety issubstituted with 1-3 F, such as when the phenyl moiety is substitutedwith 1 F).

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, wherein said phenylmoiety is substituted with 1 F.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, wherein saidphenyl moiety is substituted with 1 F.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and said ring is fused with an aryl or heteroaryl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and said ring is fused with an aryl ring, and saidresulting fused ring is optionally substituted with 1 to 5 independentlyselected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and said ring is fused with a phenyl ring, and saidresulting fused ring is optionally substituted with 1 to 5 independentlyselected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form a ring, andsaid ring is fused with an aryl or heteroaryl ring.

In another embodiment R² and R⁶ are joined together to form a ring, andsaid ring is fused with a phenyl ring.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with an aryl orheteroaryl ring, and said resulting fused ring is optionally substitutedwith 1 to 5 independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with an aryl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with a phenyl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring, and said ring is fused with an aryl or heteroarylring.

In another embodiment R² and R⁶ are joined together to form aheterocyclyl ring, and said ring is fused with a phenyl ring.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring (e.g., U is N) optionally substituted with 1 to 5independently selected R²¹ substitutents, and said ring is fused with anaryl or heteroaryl ring, and said resulting fused ring is optionallysubstituted with 1 to 5 independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring (e.g., U is N) optionally substituted with 1 to 5independently selected R²¹ substitutents, and said ring is fused with anaryl ring, and said resulting fused ring is optionally substituted with1 to 5 independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring (e.g., U is N) optionally substituted with 1 to 5independently selected R²¹ substitutents, and said ring is fused with aphenyl ring, and said resulting fused ring is optionally substitutedwith 1 to 5 independently selected R²¹ substitutents.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring (e.g., U is N), and said ring isjused with an aryl orheteroaryl ring.

In another embodiment R² and R⁶ are joined together to form apiperidinyl ring (e.g., U is N), and said ring is fused with a phenylring.

In another embodiment, R⁷ is aryl.

In another embodiment, R⁷ is an unsubstituted phenyl.

In another embodiment, R⁷ is a phenyl which is substituted with 1-4substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroarylgroups.

In another embodiment, R⁷ is 4-fluorophenyl.

In another embodiment, R⁷ is unsubstituted naphthyl.

In another embodiment, R⁷ is naphthyl which is substituted with 1-4substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroarylgroups.

In another embodiment, R⁷ is unsubstituted biphenyl.

In another embodiment, R⁷ is biphenyl which is substituted with 1-4substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁷ is R⁷ is 3-(1,1′-biphenyl)-yl.

In another embodiment, R⁷ is R⁷ is 4-(1,1′-biphenyl)-yl.

In another embodiment, R⁸ is H.

In another embodiment, R⁸ is alkyl.

In another embodiment, R⁸ is methyl.

In another embodiment, R¹⁰ is aryl.

In another embodiment, R¹⁰ is phenyl.

In another embodiment, R¹⁰ is heteroaryl.

In another embodiment R¹⁰ is aryl substituted with 1 to 3 independentlyselected R²¹ moieties.

In another embodiment R¹⁰ is aryl substituted with 1 to 3 R²¹ moieties,wherein each R²¹ moiety is the same or different —OR¹⁵ group.

In another embodiment R¹⁰ is aryl substituted with 1 R²¹ moiety.

In another embodiment R¹⁰ is aryl substituted with one R²¹ moiety, andsaid R²¹ moiety is —OR¹⁵.

In another embodiment R¹⁰ is aryl substituted with one R²¹ moiety, saidR²¹ moiety is —OR¹⁵, and said R¹⁵ is alkyl.

In another embodiment R¹⁰ is aryl substituted with one R²¹ moiety, saidR²¹ moiety is —OR¹⁵, said R¹⁵ is alkyl, and said alkyl is methyl (i.e.,said R²¹ moiety is —OCH₃).

In another embodiment R¹⁰ is phenyl substituted with 1 to 3independently selected R²¹ moieties.

In another embodiment R¹⁰ is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹ moiety is the same or different —OR¹⁵ group.

In another embodiment R¹⁰ is phenyl substituted with 1 R²¹ moiety.

In another embodiment R¹⁰ is phenyl substituted with one R²¹ moiety, andsaid R²¹ moiety is —OR¹⁵.

In another embodiment R¹⁰ is phenyl substituted with one R²¹ moiety,said R²¹ moiety is —OR¹⁵, and said R¹⁵ is alkyl.

In another embodiment R¹⁰ is phenyl substituted with one R²¹ moiety,said R²¹ moiety is —OR¹⁵, said R¹⁵ is alkyl, and said alkyl is methyl(i.e., said R²¹ moiety is —OCH₃).

In another embodiment R¹⁰ is:

In another embodiment R¹⁰ is:

wherein the —R¹⁰—R⁹ moiety is:

In another embodiment R¹⁰ is aryl substituted with 1 to 3 R²¹ moieties,wherein each R²¹ moiety is the same or different halo.

In another embodiment R¹⁰ is aryl substituted with 1 to 3 R²¹ moieties,wherein each R²¹ moiety is F.

In another embodiment R¹⁰ is aryl substituted with one R²¹ moiety, andsaid R²¹ moiety is halo.

In another embodiment R¹⁰ is aryl substituted with one R²¹ moiety, saidR²¹ moiety is -halo, and said halo is F.

In another embodiment R¹⁰ is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹ moiety is the same or different halo.

In another embodiment R¹⁰ is phenyl substituted with 1 to 3 R²¹moieties, wherein each R²¹ moiety is F.

In another embodiment R¹⁰ is phenyl substituted with one R²¹ moiety, andsaid R²¹ moiety is halo.

In another embodiment R¹⁰ is phenyl substituted with one R²¹ moiety,said R²¹ moiety is -halo, and said halo is F.

In another embodiment R¹⁰ is:

In another embodiment R¹⁰ is:

wherein the —R¹⁰—R⁹ moiety is:

In another embodiment, R¹⁰ is unsubstituted heteroaryl.

In another embodiment R¹⁰ is unsubstituted heteroaryl wherein saidheteroaryl is pyridyl.

In another embodiment R¹⁰ is:

In another embodiment R¹⁰ is:

wherein the —R¹⁰—R⁹ moiety is:

In another embodiment R¹⁰ is selected from the group consisting of:

In another embodiment, R⁹ is unsubstituted heteroaryl.

In another embodiment of this invention R⁹ is selected from the groupconsisting of heteroaryl and heteroaryl substituted with 1-3 R²¹ groups,and wherein each R²¹ is independently selected.

In another embodiment, R⁹ is heteroaryl which is substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, CN,NH₂, NH(alkyl), N(alkyl)₂, hydroxyl, alkoxy, alkyl substituted with halo(e.g., alkyl substituted with F, such as, for example, —CH₂F), and alkylsubstituted with —OR¹⁵ (such as, for example, alkyl substituted with—OR¹⁵ wherein R¹⁵ is H, that is, —CH₂OH).

In another embodiment, R⁹ is heteroaryl which is substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, CN,NH₂, NH(alkyl), N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment of this invention R⁹ is selected from the groupconsisting of imidazolyl and imidazolyl substituted with 1-3 R²¹ groups,and wherein each R²¹ is independently selected.

In another embodiment of this invention R⁹ is imidazolyl substitutedwith 1-3 R²¹ groups, and wherein each R²¹ is independently selected.

In another embodiment, R⁹ is imidazolyl which is substituted with 1-3substituents which can be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, CN,NH₂, NH(alkyl), N(alkyl)₂, hydroxyl, alkoxy, alkyl substituted with halo(e.g., alkyl substituted with F, such as, for example, —CH₂F), and alkylsubstituted with —OR¹⁵ (such as, for example, alkyl substituted with—OR¹⁵ wherein R¹⁵ is H, that is, —CH₂OH).

In another embodiment, R⁹ is imidazolyl substituted with 1-3substituents independently selected from the group consisting of halo,alkyl, CN, NH₂, NH(alkyl), N(alkyl)₂, hydroxy and alkoxy groups.

In another embodiment, R⁹ is imidazol-1-yl.

In another embodiment, R⁹ is 4-methyl-imidazol-1-yl.

In another embodiment, R⁹ is 5-chloro-4-methyl-imidazol-1-yl.

In another embodiment, R⁹ is:

In another embodiment, R⁹ is:

In another embodiment R¹⁰ is selected from the group consisting of aryland aryl substituted with one or more R²¹ groups, and R⁹ is selectedfrom the group consisting of heteroaryl and heteroaryl substituted withone or more R²¹ groups, and wherein each R²¹ is independently selected.

In another embodiment R¹⁰ is selected from the group consisting ofphenyl and phenyl substituted with 1-3 independently selected R²¹groups, and R⁹ is selected from the group consisting of imidazolyl andimidazolyl substituted with 1-3 independently selected R²¹ groups.

In another embodiment R¹⁰ is phenyl substituted with 1-3 independentlyselected R²¹ groups, and R⁹ is selected from the group consisting ofimidazolyl and imidazolyl substituted with 1-3 independently selectedR²¹ groups.

In another embodiment R¹⁰ is selected from the group consisting ofheteroaryl and heteroaryl substituted with 1-3 R²¹ groups, and the R⁹group is selected from the group consisting of heteroaryl and heteroarylsubstituted with 1-3 R²¹ groups, and wherein each R²¹ is independentlyselected.

In another embodiment R¹⁰ is selected from the group consisting ofpyridyl and pyridyl substituted with 1-3 R²¹ groups, and the R⁹ group isselected from the group consisting of imidazolyl and imidazolylsubstituted with 1-3 R²¹ groups, and wherein each R²¹ is independentlyselected.

In another embodiment R¹⁰ is pyridyl, and the R⁹ group is imidazolylsubstituted with 1-3 R²¹ groups, and wherein each R²¹ is independentlyselected.

In another embodiment the R⁹-R¹⁰-moiety is:

In another embodiment the R⁹-R¹⁰-moiety is:

In another embodiment the R⁹-R¹⁰-moiety is:

In another embodiment the R⁹-R¹⁰-moiety is:

In another embodiment R⁹-R¹⁰-moiety is:

In another embodiment R⁹-R¹⁰-moiety is:

In another embodiment, the present application discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in Formula:

wherein the various moieties are defined above.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵);

R¹ is H;

R² and R⁶ are connected to form a 4-7 membered cycloalkyl ring;

R⁷ is 3-(1,1′-biphenyl)-yl;

R⁸ is H;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R¹⁰ is phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R² and R⁶ are connected to form a 5-7 membered heterocyclyl ring;

R⁷ is phenyl;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is alkoxy-substituted phenyl; and

R⁹ is 4-methyl-imidazzol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R² and R⁶ are connected to form a piperidinyl ring;

R⁷ is 4-fluoro-phen-1-yl;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R² and R⁶ are connected to form a piperazinyl ring;

R⁷ is 4-fluoro-phen-1-yl;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is phenyl; and

R⁹ is 5-chloro-4-methyl-imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵);

R¹ is H;

R² and R⁶ are connected to form a cyclopentyl ring;

R⁷ is 3-(1,1′-biphenyl)-yl;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵);

R¹ is H;

R⁷ is alkyl;

R² and R⁶ are connected to form a cyclopentyl ring;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R² and R⁶ are connected to form a piperidinyl ring;

R⁷ is phenyl;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R⁷ is H;

R² and R⁶ are connected to form a piperazinyl ring;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is alkoxy-substituted phenyl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R⁷ is (alkoxy)aryl-alkyl-;

R² and R⁶ are connected to form a piperidinyl ring;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is (alkoxy-substituted)aryl; and

R⁹ is imidazol-1-yl.

In another embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, said compound having the general structure shown in theformula:

wherein U is C(R⁵) or N;

R¹ is H;

R² and R⁶ are connected to form a piperazinyl ring;

R⁷ is phenyl substituted with halo;

R⁵ is selected from the group consisting of H, alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-,wherein each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- can beunsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of moieties describedearlier;

R⁸ is H;

R¹⁰ is (alkoxy-substituted)aryl; and

R⁹ is imidazol-1-yl.

In one embodiment the compound of formula I is selected from the groupconsisting of:

In another embodiment the compound of formula I is selected from thegroup consisting of: compounds 1A to 16A.

In another embodiment the compound of formula I is selected from thegroup consisting of: compounds 17A to 32k

In another embodiment the compound of formula I is selected from thegroup consisting of: compounds 33A to 40A.

In another embodiment the compound of formula I is compound 1A.

In another embodiment the compound of formula I is compound 2A.

In another embodiment the compound of formula I is compound 3A.

In another embodiment the compound of formula I is compound 4A.

In another embodiment the compound of formula I is compound 5A.

In another embodiment the compound of formula I is compound 6A.

In another embodiment the compound of formula I is compound 7A.

In another embodiment the compound of formula I is compound 8A.

In another embodiment the compound of formula I is compound 9A.

In another embodiment the compound of formula I is compound 10A.

In another embodiment the compound of formula I is compound 11A.

In another embodiment the compound of formula I is compound 12A.

In another embodiment the compound of formula I is compound 13A.

In another embodiment the compound of formula I is compound 14A.

In another embodiment the compound of formula I is compound 15A.

In another embodiment the compound of formula I is compound 16A.

In another embodiment the compound of formula I is compound 17A.

In another embodiment the compound of formula I is compound 18A.

In another embodiment the compound of formula I is compound 19A.

In another embodiment the compound of formula I is compound 20A.

In another embodiment the compound of formula I is compound 21A.

In another embodiment the compound of formula I is compound 22A.

In another embodiment the compound of formula I is compound 23A.

In another embodiment the compound of formula I is compound 24A.

In another embodiment the compound of formula I is compound 25A.

In another embodiment the compound of formula I is compound 26A.

In another embodiment the compound of formula I is compound 27A.

In another embodiment the compound of formula I is compound 28A.

In another embodiment the compound of formula I is compound 29A.

In another embodiment the compound of formula I is compound 30A.

In another embodiment the compound of formula I is compound 31A.

In another embodiment the compound of formula I is compound 32A.

In another embodiment the compound of formula I is compound 33A.

In another embodiment the compound of formula I is compound 34A.

In another embodiment the compound of formula I is compound 35A.

In another embodiment the compound of formula I is compound 36A.

In another embodiment the compound of formula I is compound 37A.

In another embodiment the compound of formula I is compound 38A.

In another embodiment the compound of formula I is compound 39A.

In another embodiment the compound of formula I is compound 40A.

An illustrative group of compounds of the invention are shown in Table1.

TABLE 1 Retention Obs. Time Structure Mass (min)

433.2 3.02

535.2 2.8

— —

— —

— —

— —

— —

401.2 2.9

401.2 3.04

435.2 3.21

435.2 3.26

435.2 3.25

451.2 4.82

485.3 5.43

449.2 2.57

449.2 2.58

445.2 3.06

461.2 2.87

463.3 3.22

461.3 2.99

401.2 3.08

In one embodiment the compound of formula I is compound 1.

In another embodiment the compound of formula I is compound 2.

In another embodiment the compound of formula I is compound 3.

In another embodiment the compound of formula I is compound 4.

In another embodiment the compound of formula I is compound 5.

In another embodiment the compound of formula I is compound 6.

In another embodiment the compound of formula I is compound 7.

In another embodiment the compound of formula I is compound 9.

In another embodiment the compound of formula I is compound 10.

In another embodiment the compound of formula I is compound 11.

In another embodiment the compound of formula I is compound 12.

In another embodiment the compound of formula I is compound 13.

In another embodiment the compound of formula I is compound 14.

In another embodiment the compound of formula I is compound 15.

In another embodiment the compound of formula I is compound 16.

In another embodiment the compound of formula I is compound 17.

In another embodiment the compound of formula I is compound 18.

In another embodiment the compound of formula I is compound 19.

In another embodiment the compound of formula I is compound 20.

In another embodiment the compound of formula I is compound 21.

In another embodiment the compound of formula I is compound 22.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“At least one” means one or more than one, for example, 1, 2 or 3, or inanother example, 1 or 2, or in another example 1.

“One or more” with reference to the use of the compounds of thisinvention means that one or more than one compound is used, for example,1, 2 or 3, or in another example, 1 or 2, or in another example 1.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

It is noted that the carbons of formula I and other formulas herein maybe replaced with 1 to 3 silicon atoms so long as all valencyrequirements are satisfied.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., ═N—OH),—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, carboxy and —C(O)O-alkyl. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms.

The aryl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. Non- limiting examples of suitable aryl groups includephenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine. “Halo” refers to fluoro, chloro, bromoor iodo.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl), oxime(e.g., ═N—OH), Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and—SO₂NY₁Y₂, wherein Y₁ and Y₂ can be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean asingle moiety which simultaneously replaces two available hydrogens ontwo adjacent carbon atoms (one H on each carbon) on a ring system.Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH₃)₂—and the like which form moieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a heterocyclyl ring wherein a single moiety (e.g., ═O)simultaneously replaces two available hydrogens on the same carbon atomon a ring system. An example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent, moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl. “Arylsulfonyl” means an aryl-S(O₂)— group. Thebond to the parent moiety is through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound' or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidine-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1((C₁-C₆)alkanoyloxy)ethyl, (C₁C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide,enol, keto or imino ether). All such tautomeric forms are contemplatedherein as part of the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ¹⁸F, and ³⁵Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention can have pharmacologicalproperties; in particular, the compounds of Formula I can be modulatorsof gamma secretase (including inhibitors, antagonists and the like).

More specifically, the compounds of Formula I can be useful in thetreatment of a variety of disorders of the central nervous systemincluding, for example, including, but not limited to, Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration and the like.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition of the central nervous system byadministering a therapeutically effective amount of at least onecompound of Formula I, or a pharmaceutically acceptable salt, solvate,ester or prodrug of said compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula I. An especially preferred dosage is about 0.01 to25 mg/kg of body weight/day of a compound of Formula I, or apharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more additionalagents listed above.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more compoundsselected from the group consisting of Aβ antibody inhibitors, gammasecretase inhibitors and beta secretase inhibitors.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, andan amount of one or more additional agents listed above wherein theamounts of the compounds/treatments result in desired therapeuticeffect.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. Certain assays areexemplified later in this document.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug of said compound and at leastone pharmaceutically acceptable carrier.

Other embodiments of this invention are directed to pharmaceuticallyacceptable salts of any one of the embodiments above directed to any oneof compounds 1 to 7 and 9 to 22.

Other embodiments of this invention are directed to pharmaceuticallyacceptable esters of any one of the embodiments above directed to anyone of compounds 1 to 7 and 9 to 22.

Other embodiments of this invention are directed to solvates of any oneof the embodiments above directed to any one of compounds 1 to 7 and 9to 22.

One embodiment of this invention is directed to a compound of formula I.

Another embodiment of this invention is directed to a pharmaceuticallyacceptable salt of a compound of formula I.

Another embodiment of this invention is directed to a pharmaceuticallyacceptable ester of a compound of formula I.

Another embodiment of this invention is directed to a solvate of acompound of formula I.

Another embodiment of this invention is directed to a compound offormula I in isolated form.

Another embodiment of this invention is directed to a compound offormula I in pure form.

Another embodiment of this invention is directed to a compound offormula I in pure and isolated form.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula I and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of a pharmaceuticallyacceptable salt of one or more (e.g., one) compounds of formula I and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of a pharmaceuticallyacceptable ester of one or more (e.g., one) compounds of formula I and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of a solvate of one or more(e.g., one) compounds of formula I and a pharmaceutically acceptablecarrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula I, and an effective amount of one or more (e.g.,one) other pharmaceutically active ingredients (e.g.,) drugs, and apharmaceutically acceptable carrier. Examples of the otherpharmaceutically active ingredients include, but are not limited todrugs selected form the group consisting of: (a) drugs useful for thetreatment of Alzheimer's disease, (b) drugs useful for inhibiting thedeposition of amyloid protein (e.g., amyloid beta protein) in, on oraround neurological tissue (e.g., the brain), (c) drugs useful fortreating neurodegenerative diseases, and (d) drugs useful for inhibitinggamma-secretase.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula I, and effective amount of one or more BACEinhibitors, and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula I, and effective amount of one or morecholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesteraseinhibitors), and a pharmaceutically acceptable carrier.

The compounds of formula I can be useful as gamma secretase modulatorsand can be useful in the treatment and prevention of diseases such as,for example, central nervous system disorders such as Alzheimers diseaseand Downs Syndrome.

Thus, another embodiment of this invention is directed to a method formodulating (including inhibiting, antagonizing and the like)gamma-secretase comprising administering an effective amount of one ormore (e.g., one) compounds of formula I to a patient in need of suchtreatment.

Another embodiment of this invention is directed to a method formodulating (including inhibiting, antagonizing and the like)gamma-secretase, comprising administering an effective amount of acompound of formula I to a patient in need of treatment.

Another embodiment of this invention is directed to a method of treatingone or more neurodegenerative diseases, comprising administering aneffective amount of one or more (e.g., one) compounds of formula I to apatient in need of treatment.

Another embodiment of this invention is directed to a method of treatingone or more neurodegenerative diseases, comprising administering aneffective amount of a compound of formula I to a patient in need oftreatment.

Another embodiment of this invention is directed to a method ofinhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain),comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

Another embodiment of this invention is directed to a method ofinhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain),comprising administering an effective amount of a compound of formula Ito a patient in need of treatment. Another embodiment of this inventionis directed to a method of treating

Alzheimer's disease, comprising administering an effective amount of oneor more (e.g., one) compounds of formula I to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of acompound of formula I to a patient in need of treatment.

This invention also provides combination therapies for (1) modulatinggamma-secretase, or (2) treating one or more neurodegenerative diseases,or (3) inhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain), or (4)treating Alzheimer's disease. The combination therapies are directed tomethods comprising the administration of an effective amount of one ormore (e.g. one) compounds of formula I and the administration of aneffective amount of one or more (e.g., one) other pharmaceutical activeingredients (e.g., drugs). The compounds of formula I and the otherdrugs can be administered separately (i.e., each is in its own separatedosage form), or the compounds of formula I can be combined with theother drugs in the same dosage form.

Thus, other embodiments of this invention are directed to any one of themethods of treatment, or methods of inhibiting, described herein,wherein an effective amount of the compound of formula I is used incombination with an effective amount of one or more otherpharmaceutically active ingredients selected from the group consistingof: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists(e.g., m₁ agonists or m₂ antagonists), cholinesterase inhibitors (e.g.,acetyl- and/or butyrylchlolinesterase inhibitors); gamma secretaseinhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors;non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptorantagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; an antibiotic; growth hormone secretagogues; histamine H3antagonists; AMPA agonists; PDE4 inhibitors; GABA_(A) inverse agonists;inhibitors of amyloid aggregation; glycogen synthase kinase betainhibitors; promoters of alpha secretase activity; PDE-10 inhibitors andcholesterol absorption inhibitors (e.g., ezetimibe).

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more (e.g., one) compounds of formula I, in combination with aneffective (i.e., therapeutically effective) amount of one or morecholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of acompound of formula I, in combination with an effective amount of one ormore (e.g., one) cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinylimethyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more (e.g., one) compounds of formula I, in combination with aneffective amount of one or more compounds selected from the groupconsisting of Aβ antibody inhibitors, gamma secretase inhibitors andbeta secretase inhibitors.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more (e.g., one) compounds of formula I, in combination with aneffective amount of one or more BACE inhibitors.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof Exelon (rivastigmine).

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof Cognex (tacrine).

Another embodiment of this invention is directed to a method of treating

Alzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof a Tau kinase inhibitor.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk5inhibitor, ERK inhibitor).

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective amount of one or more compounds offormula I, in combination with an effective amount of one anti-Abetavaccination (active immunization).

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more APP ligands.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more agents that upregulate insulin degrading enzyme and/orneprilysin.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more. compounds of formula I, in combination with an effective amountof one or more cholesterol lowering agents (for example, statins such asAtorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin,Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorptioninhibitor such as Ezetimibe).

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective amount of one or more compounds offormula I, in combination with an effective amount of one or morefibrates (for example, clofibrate, Clofibride, Etofibrate, AluminiumClofibrate).

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more LXR agonists.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more LRP mimics.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more 5-HT6 receptor antagonists.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more nicotinic receptor agonists.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more H3 receptor antagonists.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective amount of one or more compounds offormula I, in combination with an effective amount of one or morehistone deacetylase inhibitors.

Another embodiment of this invention is directed to a method of treating

Alzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more hsp90 inhibitors.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more m1 muscarinic receptor agonists.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more 5-HT6 receptor antagonists mGluR1 or mGluR5 positiveallosteric modulators or agonists

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more mGluR2/3 antagonists.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more anti-inflammatory agents that can reduceneuroinflammation.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of formula I, in combination with an effective amountof one or more Prostaglandin EP2 receptor antagonists.

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective amount of one or more compounds offormula I, in combination with an effective amount of one or more PAI-1inhibitors:

This invention also provides a method of treating Alzheimer's disease,comprising administering an effective amount of one or more compounds offormula I, in combination with an effective amount of one or more agentsthat can induce Abeta efflux such as gelsolin.

This invention also provides a method of treating Downs syndrome,comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective amount of a compound of formula Ito a patient in need of treatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective amount of one or more (e.g., one)compounds of formula I, in combination with an effective amount of oneor more cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

This invention also provides a method of treating Downs syndrome,comprising administering an effective amount of a compound of formula I,in combination with an effective amount of one or more (e.g., one)cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

This invention also provides a method of treating mild cognitiveimpairment, comprising administering an effective amount of one or more(e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating glaucoma, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating cerebral amyloidangiopathy, comprising administering an effective amount of one or more(e.g., one) compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating stroke, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating dementia, comprisingadministering an effective amount of one or more (e.g., one) compoundsof formula I to a patient in need of treatment.

This invention also provides a method of treating microgliosis,comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating brain inflammation,comprising administering an effective amount of one or more (e.g., one)compounds of formula I to a patient in need of treatment.

This invention also provides a method of treating olfactory functionloss, comprising administering an effective amount of one or more (e.g.,one) compounds of formula I to a patient in need of treatment.

This invention also provides combinations (i.e., pharmaceuticalcompositions) comprising an effective amount of one or more (e.g., one)compounds of formula I, in combination with an effective amount of oneor more compounds selected from the group consisting of cholinesteraseinhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), Aβ antibody inhibitors,gamma secretase inhibitors and beta secretase inhibitors. Thepharmaceutical compositions also comprise a pharmaceutically acceptablecarrier.

This invention also provides a kit comprising, in separate containers,in a single package, pharmaceutical compositions for use in combination,wherein one container comprises an effective amount of a compound offormula I in a pharmaceutically acceptable carrier, and anothercontainer (i.e., a second container) comprises an effective amount ofanother pharmaceutically active ingredient (as described above), thecombined quantities of the compound of formula I and the otherpharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid protein(e.g., amyloid beta protein) in, on or around neurological tissue (e.g.,the brain), or (c) treat neurodegenerative diseases, or (d) modulate theactivity of gamma-secretase.

Another embodiment of this invention is directed to a pharmaceuticallyacceptable salt of a compound of formula (I), said compound of formula(I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a pharmaceuticallyacceptable ester of a compound of formula (I), said compound of formula(I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a solvate of acompound of formula (I), said compound of formula (I) being selectedfrom the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a compound offormula (I) in isolated form, said compound of formula (I) beingselected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a compound offormula (I) in pure form, said compound of formula (I) being selectedfrom the group consisting of: said compound of formula (I) beingselected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a compound offormula (I) in pure and isolated form, said compound of formula (I)being selected from the group consisting of: said compound of formula(I) being selected from the group consisting of: 1A to 40A.

Another embodiment is directed to a pharmaceutical compositioncomprising an effective amount of one or more (e.g., one) compounds offormula (I) and a pharmaceutically acceptable carrier, said compound offormula (I) being selected from the group consisting of: said compoundof formula (I) being selected from the group consisting of: 1A to 40A.

Another embodiment is directed to a pharmaceutical compositioncomprising an effective amount of a pharmaceutically acceptable salt ofone or more (e.g., one) compounds of formula (I) and a pharmaceuticallyacceptable carrier, said compound of formula (I) being selected from thegroup consisting of: said compound of formula (I) being selected fromthe group consisting of: 1A to 40A.

Another embodiment is directed to a pharmaceutical compositioncomprising an effective amount of a pharmaceutically acceptable ester ofone or more (e.g., one) compounds of formula (I) and a pharmaceuticallyacceptable carrier, said compound of formula (I) being selected from thegroup consisting of:

said compound of formula (I) being selected from the group consistingof: 1A to 40A.

Another embodiment is directed to a pharmaceutical compositioncomprising an effective amount of a solvate of one or more (e.g., one)compounds of formula (I) and a pharmaceutically acceptable carrier, saidcompound of formula (I) being selected from the group consisting of:said compound of formula (I) being selected from the group consistingof: 1A to 40A.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula (I), and an effective amount of one or more (e.g.,one) other pharmaceutically active ingredients (e.g., drugs), and apharmaceutically acceptable carrier. Examples of the otherpharmaceutically active ingredients include, but are not limited todrugs selected form the group consisting of: (a) drugs useful for thetreatment of Alzheimer's disease, (b) drugs useful for inhibiting thedeposition of amyloid protein (e.g., amyloid beta protein) in, on oraround neurological tissue (e.g., the brain), (c) drugs useful fortreating neurodegenerative diseases, and (d) drugs useful for inhibitinggamma-secretase, said compound of formula (I) being selected from thegroup consisting of: said compound of formula (I) being selected fromthe group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds of formula (I), and effective amount of one or more BACEinhibitors, and a pharmaceutically acceptable carrier, said compound offormula (I) being selected from the group consisting of: said compoundof formula (I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, and aneffective amount of one or more cholinesterase inhibitors (e.g., acetyl-and/or butyrylchlolinesterase inhibitors), and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more muscarinic antagonists (e.g., m₁agonists or m₂ antagonists), and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of Exelon (rivastigmine), and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of Cognex (tacrine), and a pharmaceutically acceptablecarrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of a Tau kinase inhibitor, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more Tau kinase inhibitor (e.g., GSK3betainhibitor, cdk5 inhibitor, ERK inhibitor), and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one anti-Abeta vaccine (active immunization), and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more APP ligands, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: consisting of: 1A to40A, and effective amount of one or more agents that upregulate insulindegrading enzyme and/or neprilysin, and a pharmaceutically acceptablecarrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more cholesterol lowering agents (forexample, statins such as Atorvastatin, Fluvastatin, Lovastatin,Mevastatin, Pitavastatin, Pravastatine, Rosuvastatin, Simvastatin, andcholesterol absorption inhibitor such as Ezetimibe), and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: consisting of: 1A to40A, and effective amount of one or more fibrates (for example,clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate), and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: consisting of: 1A to40A, and effective amount of one or more LXR agonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more LRP mimics, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more 5-HT6 receptor antagonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: consisting of: 1A to40A, and effective amount of one or more nicotinic receptor agonists,and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more H3 receptor antagonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more histone deacetylase inhibitors, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more hsp90 inhibitors, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more m1 muscarinic receptor agonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more 5-HT6 receptor antagonists mGluR1 ormGluR5 positive allosteric modulators or agonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more one mGluR2/3 antagonists, and apharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more anti-inflammatory agents that can reduceneuroinflammation, and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more Prostaglandin EP2 receptor antagonists,and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more PAI-1 inhibitors, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of one or more (e.g., one)compounds selected from the group consisting of: 1A to 40A, andeffective amount of one or more agents that can induce Abeta efflux suchas gelsolin, and a pharmaceutically acceptable carrier.

The compounds of formulas (I) selected from the group consisting of: 1Ato 40A can be useful as gamma secretase modulators and can be useful inthe treatment and prevention of diseases such as, for example, centralnervous system disorders (such as Alzheimers disease and DownsSyndrome), and treating mild cognitive impairment, glaucoma, cerebralamyloid angiopathy, stroke, dementia, microgliosis, brain inflammation,and olfactory function loss. Thus, another embodiment of this inventionis directed to a method for modulating (including inhibiting,antagonizing and the like) gamma-secretase comprising administering aneffective (i.e., therapeutically effective) amount of one or more (e.g.,one) compounds of formula (I) to a patient in need of such treatment,said compound of formula (I) being selected from the group consistingof: 1A to 40A.

Another embodiment of this invention is directed to a method formodulating (including inhibiting, antagonizing and the like)gamma-secretase, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) to apatient in need of treatment, said compound of formula (I) beingselected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method of treatingone or more neurodegenerative diseases, comprising administering aneffective (i.e., therapeutically effective) amount of one or more (e.g.,one) compounds of formula (I) to a patient in need of treatment, saidcompound of formula (I) being selected from the group consisting of: 1Ato 40A.

Another embodiment of this invention is directed to a method of treatingone or more neurodegenerative diseases, comprising administering aneffective (i.e., therapeutically effective) amount of a compound offormula (I) to a patient in need of treatment, said compound of formula(I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method ofinhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain),comprising administering an effective (i.e., therapeutically effective)amount of one or more (e.g., one) compounds of formula (I) to a patientin need of treatment, said compound of formula (I) being selected fromthe group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method ofinhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain),comprising administering an effective (i.e., therapeutically effective)amount of a compound of formula (I) to a patient in need of treatment,said compound of formula (I) being selected from the group consistingof: 1A to 40A.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) to a patient in need of treatment, said compound offormula (I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) to apatient in need of treatment, said compound of formula (I) beingselected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method of treatingmild cognitive impairment, glaucoma, cerebral amyloid angiopathy,stroke, dementia, microgliosis, brain inflammation, or olfactoryfunction loss, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) to a patient in need of treatment, said compound offormula (I) being selected from the group consisting of: 1A to 40A.

Another embodiment of this invention is directed to a method of treatingmild cognitive impairment, glaucoma, cerebral amyloid angiopathy,stroke, dementia, microgliosis, brain inflammation, or olfactoryfunction loss, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) to apatient in need of treatment, said compound of formula (I) beingselected from the group consisting of: 1A to 40A.

This invention also provides combination therapies for (1) modulatinggamma-secretase, or (2) treating one or more neurodegenerative diseases,or (3) inhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain), or (4)treating Alzheimer's disease. The combination therapies are directed tomethods comprising the administration of one or more (e.g. one)compounds of formula (I), and the administration of one or more (e.g.,one) other pharmaceutical active ingredients (e.g., drugs). Thecompounds of formula (I), and the other drugs can be administeredseparately (i.e., each is in its own separate dosage form), or thecompounds of formula (I) can be combined with the other drugs in thesame dosage form.

Thus, other embodiments of this invention are directed to any one of themethods of treatment, or methods of inhibiting, described herein,wherein the compounds of formula (I) are used in combination with aneffective amount of one or more other pharmaceutically activeingredients selected from the group consisting of: BACE inhibitors (betasecretase inhibitors); muscarinic antagonists (e.g., m₁ agonists or m₂antagonists); cholinesterase inhibitors (e.g., acetyl- and/orbutyrylchlolinesterase inhibitors); gamma secretase inhibitors; gammasecretase modulators; HMG-CoA reductase inhibitors; non-steroidalanti-inflammatory agents; N-methyl-D-aspartate receptor antagonists;anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptoragonists; CB1 receptor inverse agonists or CB1 receptor antagonists; anantibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPAagonists; PDE4 inhibitors; GABA_(A) inverse agonists; inhibitors ofamyloid aggregation; glycogen synthase kinase beta inhibitors; promotersof alpha secretase activity; PDE-10 inhibitors; Exelon (rivastigmine);Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP ligands; agentsthat upregulate insulin cholesterol lowering agents (for example,statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin,Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterolabsorption inhibitors (such as Ezetimibe); fibrates (such as, forexample, for example, clofibrate, Clofibride, Etofibrate, and AluminiumClofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors;m1 muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1;mGluR5; positive allosteric modulators or agonists; mGluR2/3antagonists; anti-inflammatory agents that can reduce neuroinflammation;Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; and agentsthat can induce Abeta efflux such as gelsolin.

This invention also provides combination therapies for (1) modulatinggamma-secretase, or (2) treating one or more neurodegenerative diseases,or (3) inhibiting the deposition of amyloid protein (e.g., amyloid betaprotein) in, on or around neurological tissue (e.g., the brain), or (4)treating Alzheimer's disease. The combination therapies are directed tomethods comprising the administration of one or more (e.g. one)compounds of formula (I) selected from the group consisting of: 1A to40A, and the administration of one or more (e.g., one) otherpharmaceutical active ingredients (e.g., drugs). The compounds offormula 1A to 40A, and the other drugs can be administered separately(i.e., each is in its own separate dosage form), or the compounds offormula 1A to 40A can be combined with the other drugs in the samedosage form.

Thus, other embodiments of this invention are directed to any one of themethods of treatment, or methods of inhibiting, described herein,wherein the compounds of formula (I), selected from the group consistingof: 1A to 40A are used in combination with an effective amount of one ormore other pharmaceutically active ingredients selected from the groupconsisting of: BACE inhibitors (beta secretase inhibitors), muscarinicantagonists (e.g., m₁ agonists or m₂ antagonists), cholinesteraseinhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors);gamma secretase inhibitors; gamma secretase modulators; HMG-CoAreductase inhibitors; non-steroidal anti-inflammatory agents;N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies;vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptorinverse agonists or CB1 receptor antagonists; an antibiotic; growthhormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors; Exelon (rivastigmine);Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP ligands; agentsthat upregulate insulin cholesterol lowering agents (for example,statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin,Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterolabsorption inhibitors (such as Ezetimibe); fibrates (such as, forexample, for example, clofibrate, Clofibride, Etofibrate, and AluminiumClofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors;m1 muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1;mGluR5; positive allosteric modulators or agonists; mGluR2/3antagonists; anti-inflammatory agents that can reduce neuroinflammation;Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; and agentsthat can induce Abeta efflux such as gelsolin.

Other embodiments of this invention are directed to any one of themethods of treatment, or methods of inhibiting, described herein,wherein the compounds of formula (I), selected from the group consistingof: 1A to 40A are used in combination with an effective amount of one ormore other pharmaceutically active ingredients selected from the groupconsisting of: BACE inhibitors (beta secretase inhibitors), muscarinicantagonists (e.g., m₁ agonists or m₂ antagonists), cholinesteraseinhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors);gamma secretase inhibitors; gamma secretase modulators; HMG-CoAreductase inhibitors; non-steroidal anti-inflammatory agents;N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies;vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptorinverse agonists or CB1 receptor antagonists; an antibiotic; growthhormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors; and cholesterol absorptioninhibitors (e.g., ezetimibe).

Other embodiments of this invention are directed to any one of themethods of treatment, or methods of inhibiting, described herein,wherein the compounds of formula (I), selected from the group consistingof: 1A to 40A are used in combination with an effective amount of one ormore other pharmaceutically active ingredients selected from the groupconsisting of: Exelon (rivastigmine); Cognex (tacrine); Tau kinaseinhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERKinhibitors); anti-Abeta vaccine; APP ligands; agents that upregulateinsulin cholesterol lowering agents (for example, statins such asAtorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin,Pravastatin, Rosuvastatin, Simvastatin);cholesterol absorptioninhibitors (such as Ezetimibe); fibrates (such as, for example, forexample, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate);LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptorantagonists; histone deacetylase inhibitors; hsp90 inhibitors; m1muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1;mGluR5; positive allosteric modulators or agonists; mGluR2/3antagonists; anti-inflammatory agents that can reduce neuroinflammation;Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; and agentsthat can induce Abeta efflux such as gelsolin.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: 1A to 40A, incombination with an effective (i.e., therapeutically effective) amountof one or more cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) selectedfrom the group consisting of: 1A to 40A, in combination with aneffective (i.e., therapeutically effective) amount of one or more (e.g.,one) cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e., donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride), to a patient in need of treatment.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: in combinationwith an effective (i.e., therapeutically effective) amount of one ormore compounds selected from the group consisting of Aβ antibodyinhibitors, gamma secretase inhibitors and beta secretase inhibitors.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: 1A to 40A, incombination with an effective (i.e., therapeutically effective) amountof one or more BACE inhibitors.

Another embodiment of this invention is directed to a method of treatingAlzheimer's disease, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) selectedfrom the group consisting of: 1A to 40A, and the Compound of Example 1,in combination with an effective (i.e., therapeutically effective)amount of one or more BACE inhibitors.

Another embodiment of this invention is directed to a method of treatingDowns syndrome, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: 1A to 40A to apatient in need of treatment.

Another embodiment of this invention is directed to a method of treatingDowns syndrome, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) selectedfrom the group consisting of: 1A to 40A, to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingDowns syndrome, comprising administering an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: 1A to 40A, incombination with an effective (i.e., therapeutically effective) amountof one or more cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), to a patient in need oftreatment.

Another embodiment of this invention is directed to a method of treatingDowns syndrome, comprising administering an effective (i.e.,therapeutically effective) amount of a compound of formula (I) selectedfrom the group consisting of: 1A to 40A, in combination with aneffective (i.e., therapeutically effective) amount of one or more (e.g.,one) cholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, i.e., donepezil hydrochloride, available as the Aricept®brand of donepezil hydrochloride), to a patient in need of treatment.

Another embodiment of this invention is directed to combinations (i.e.,pharmaceutical compositions) comprising an effective (i.e.,therapeutically effective) amount of one or more (e.g., one) compoundsof formula (I) selected from the group consisting of: 1A to 40A incombination with an effective (i.e., therapeutically effective) amountof one or more compounds selected from the group consisting ofcholinesterase inhibitors (such as, for example,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride, available asthe Aricept® brand of donepezil hydrochloride), Aβ antibody inhibitors,gamma secretase inhibitors and beta secretase inhibitors. Thepharmaceutical compositions also comprise a pharmaceutically acceptablecarrier.

This invention also provides a kit comprising, in separate containers,in a single package, pharmaceutical compositions for use in combination,wherein one container comprises an effective amount of one or more(e.g., one) compounds of formula (I) (e.g., compounds selected from thegroup consisting of: 1A to 40A in a pharmaceutically acceptable carrier,and another container (i.e., a second container) comprises an effectiveamount of another pharmaceutically active ingredient (as describedabove), the combined quantities of the compounds of formula (I) and theother pharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid protein(e.g., amyloid beta protein) in, on or around neurological tissue (e.g.,the brain), or (c) treat neurodegenerative diseases, or (d) modulate theactivity of gamma-secretase.

This invention also provides a kit comprising, in separate containers,in a single package, pharmaceutical compositions for use in combination,wherein one container comprises an effective amount of a compoundselected from the group consisting of the compounds of formulas (I)(e.g. the compounds selected from the group consisting of: 1A to 40A) ina pharmaceutically acceptable carrier, and another container (i.e., asecond container) comprises an effective amount of anotherpharmaceutically active ingredient (as described above), the combinedquantities of the compound of formulas (I) and the otherpharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid protein(e.g., amyloid beta protein) in, on or around neurological tissue (e.g.,the brain), or (c) treat neurodegenerative diseases, or (d) modulate theactivity of gamma-secretase.

Other embodiments of this invention are directed to any one of the abovemethods of treatment, pharmaceutical compositions, or kits wherein thecompound of formula I is any one of the compounds 1 to 7 and 9 to 22

Examples of cholinesterase inhibitors are tacrine, donepezil,rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine,donepezil, rivastigmine and galantamine being preferred.

Examples of m₁ agonists are known in the art. Examples of m₂ antagonistsare also known in the art; in particular, m₂ antagonists are disclosedin U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 6,043,255; 5,952,349;5,935,958; 6,066,636; 5,977,138; 6,294,554; 6,043,255; and 6,458,812;and in WO 03/031412, all of which are incorporated herein by reference.

Examples of BACE inhibitors include those described in: US2005/0119227published Jun. 2, 2005 (see also WO2005/016876 published Feb. 24, 2005),US2005/0043290 published Feb. 24, 2005 (see also WO2005/014540 publishedFeb. 17, 2005), WO2005/058311 published Jun. 30. 2005 (see alsoUS2007/0072852 published Mar. 29, 2007), US2006/0111370 published May25, 2006 (see also WO2006/065277 published Jun. 22, 2006), U.S.application Ser. No. 11/710,582 filed Feb. 23, 2007, US2006/0040994published Feb. 23, 2006 (see also WO2006/014762 published Feb. 9, 2006),WO2006/014944 published Feb. 09, 2006 (see also US2006/0040948 publishedFeb. 23, 2006), WO2006/138266 published Dec. 28, 2006 (see alsoUS2007/0010667 published Jan. 11, 2007), WO2006/138265 published Dec.28, 2006, WO2006/138230 published Dec. 28, 2006, WO2006/138195 publishedDec. 28, 2006 (see also US2006/0281729 published Dec. 14, 2006),WO2006/138264 published Dec. 28, 2006 (see also US2007/0060575 publishedMar. 15, 2007), WO2006/138192 published Dec. 28, 2006 (see alsoUS2006/0281730 published Dec. 14, 2006), WO2006/138217 published Dec.28, 2006 (see also US2006/0287294 published Dec. 21, 2006),US2007/0099898 published May 3, 2007 (see also WO2007/050721 publishedMay 3, 2007), WO2007/053506 published May 10, 2007 (see alsoUS2007/099875 published May 3, 2007), U.S. application Ser. No.11/759,336 filed Jun. 7, 2007, U.S. application Ser. No. 60/874362 filedDec. 12, 2006, and U.S. Application Ser. No. 60/874,419 filed Dec. 12,2006, the disclosures of each being incorporated incorporated herein byreference thereto.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable salt,solvate, ester or prodrug of said compound and an amount of at least oneadditional agent listed above, wherein the amounts of the two or moreingredients result in desired therapeutic effect.

The invention disclosed herein is exemplified by the following examplewhich should not be construed to limit the scope of the disclosure.Alternative mechanistic pathways and analogous structures will beapparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN, 7.5min—10% CH₃CN, 9 min—stop. The observed parent ion is given.

Examples Method A, Compound 1 of Table 1

Method A, Step 1

The following method was adapted for the oxadiazoline synthesis (Tsuge,Otohiko; Kanemasa, Shuji; Suga, Hiroyuki; Nakagawa, Norihiko. Bulletinof the Chemical Society of Japan (1987), 60(7), 2463-73).

Compound A1 (R⁸═H, R¹⁹=3-MeO-Phenyl, R⁹=4-(4-Methylimidazol-1-yl), 3 g)and A2 (4.2 g) in 135 ml of anhydrous THF was heated at 100° C. in asealed tube under nitrogen overnight. Solvent was evaporated and residuechromatographed using a silica gel column eluted with EtOAc/Hexane togive 2.7 g of A3 (R¹═H, R⁸═H, R¹⁰=3-OMePhenyl,R⁹=4-(4-Methyl-imidazol-1-yl)).

Method A, Step 2

A3 (R¹═H, R⁸═H, R¹⁰=3-MeO-Phenyl, R⁹=4-(4-Methyl-imidazol-1-yl), 2.7 g)and potassium acetate (1.4 g) in 120 mL MeOH was cooled to 0° C. beforehydoxylamine hydrochloride (1 g) was added. The reaction mixture wasstirred for 90 min before the solvent was evaporated. The residue waspartitioned in EtOAc and brine. The organic layer was dried overanhydrous Na₂SO₄, The crude was purified on C18 reverse phase column togive 1 g of A4 (R¹═H, R⁸═H, R¹⁰=3-MeO-Phenyl,R⁹=4-(4-Methyl-imidazol-1-yl)).

MS (M+1): 258.

Method A, Step 3

To the solution of A5 (1.98 g, 9.94 mmol) in 30 ml of anhydrous THF at−78° C. was slowly added A6 (R⁷=4-Fluorophenyl, 11.9 ml, 11.92 mmol)over 20 minutes. The mixture was warmed up to r.t. and stirred at r.t.overnight. The reaction was quenched by adding 2M HCl aqueous solutionto PH=3, the mixture was extracted with CH₂Cl₂, washed with brine, driedover Na₂SO₄, filtered. The filtrate was concentrated and purified byIsco using 20% of EtOAc/Hexane. Yield: 1.4 g of A7. ¹H NMR (CDCl₃ 400MHz): 7.96 (m, 2H), 7.10 (t, J=8.8 Hz, 2H), 4.64 (bs, 1H), 3.15 (m, 2H),2.95 (t, J=7.3 Hz, 2H), 1.75 (m, 2H), 1.55 (m, 2H), 1.42 (s, 9H).

Method A, Step 4

To the solution of A7 (R⁷=4-Fluorophenyl, 0.9 g, 3.05 mmol) in 3 ml ofTFA was added 3A molecular sieves. After stirring at room temperaturefor 4 h, the reaction was neutralized by adding saturated NaHCO₃ aqueoussolution to PH=10, the mixture was extracted with CH₂Cl₂, washed withbrine, dried over Na₂SO₄, and filtered. The residue is pure A8. Yield:0.46 g. MH⁺: 178.2.

Method A, Step 5

To the solution of A4 (0.098 g, 0.381 mmol) in 2 ml of DCM was added NCS(0.051 g, 0.381 mmol) at 0° C. After stirring at 0° C. for 1 h, A8(0.068 g, 0.381 mmol) and Et₃N (0.08 ml, 0.572 mmol) in 1 ml of DCM wasadded at 0° C. the mixture was then stirred at r.t. for 24 h, extractedwith CH₂Cl₂ and brine, dried over Na₂SO₄, filtered, concentrated andpurified by reverse-phase HPLC to give 0.035 g of A9 (R¹═R⁸═H,R¹⁰=3-OMePhenyl, R⁹=4-(4-Methyl-imidazol-1-yl, R⁷=4-Fluorophenyl). ¹HNMR (CDCl₃ 400 MHz): 7.74 (s, 1H), 7.64 (m, 2H), 7.4 (d, J=16.4 Hz, 1H),7.26 (m, 1H), 7.17 (dd, J=8.2 and 1.6 Hz, 1H), 7.07-7.13 (m, 3H), 6.94(s, 1H), 6.52 (d, J=16.4 Hz, 1H), 3.90 (s, 3H), 3.65 (m, 1H), 3.08 (m,1H), 2.19-2.40 (m, 5H), 1.90 (m, 1H), 1.60 (m, 2H), 1.48(m, 1H). MS(M+1): 433.2.

The compounds 1-7 and 9-15 in Table 1 were synthesized using methodssimilar to that of Method A.

Method B, Compound 18 of Table 1

Method B, Step 1: 7-Fluoro-3,4,4a,5-tetrahydro-2H-indeno[1,2-b]pyridine(B1)

3-Bromopropylamine (4.7 g. 21.7 mmole) and 5-Fluoro-1-indanone (2.5 g,16.7 mmole) were dissolved in 50 ml DMF and the reaction was cooled to0° C. Triethylamine (13.5 g, 133 mmole) was added. 20 ml DCM was alsoadded to help with the stirring. Titanium chloride (1M in DCM, 15 ml)was then added and the ice bath was removed. The reaction was stirred atroom temperature overnight. 200 ml ether was added and the reaction wasfiltered though a Celite cake. The filtrate was concentrated to drynessunder vacuum. The residue was dissolved in 200 ml ether and washed withbrine (2×200 ml). The organic layer was dried over sodium sulfate andconcentrated to dryness. 2.6 g Black oil was obtained and it was used innext step without further purification.

Method B, Step 2: Step 2: Diethyl((7aS,12a1R)-10-fluoro-6,7,7a,8-tetrahydro-5H-indeno[1,2-b][1,2,4]oxadiazolo[4,5-a]pyridin-3-yl)methylphosphonate(B2)

Diethyl 2-(hydroxyimino)ethylphosphonate (1.87 g, 9.63 mmole) wasdissolved in 30 ml DMF and the reaction was cooled to 0° C.N-bromosuccinimide (1.71 g, 9.63 mmole) in 15 ml DMF was added and thereaction was stirred at 0° C. for half hour. B1 (2.6 g, 9.63 mmole) andtriethylamine (0.96 g, 9.6 mmole) in 25 ml DMF was added. The reactionwas stirred at room temperature overnight. DMF was removed and theresidue was partitioned between 100 ml EtOAc and 100 ml water. Theorganic layer was washed with water (2×100 ml), dried with Na₂SO₄ andconcentrated. The residue was purified by column (EtOAc/hexane from25/75 to 100/0 in 45 minutes, 120 g silica). Yield: 0.64 g, 17%. ¹H NMR(CDCl₃ 400 MHz): 7.43 (dd, J=8.1, 5.1 Hz, 1H), 6.97 (m, 2H), 4.23 (m,4H), 3.76 (m, 1H), 3.26 (dd, J=15.4 and 5.9 Hz, 1H), 2.80-3.10 (m, 3H),2.55 (m, 1H), 2.34 (d, J=16.1 Hz, 1H), 2.30, (m, 1H), 1.50 (m, 2H), 1.38(t, J=7.3 Hz, 6H), 1.05 (m, 1H).

Method B, Step 3:(7aS,12a1R)-10-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)styryl)-6,7,7a,8-tetrahydro-5H-indeno[1,2-b][1,2,4]oxadiazolo[4,5-a]pyridine(B3, R⁹=4-(4-Methylimidazol-1-yl), R¹⁰=3-MeO-Phenyl)

B2 (0.24 g, 0.63 mmole) was dissolved in THF and the reaction was cooledto −78° C. n-Butyllithium (2.5 ml in Hexane, 0.28 ml) was added and thereaction was stirred at −78° C. for 30 minutes.3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.136 g, 0.63mmole) in 10 ml THF (Pre-cooled to −78° C.) was added. The reaction wasstirred at −78° C. for 1 hour, then at room temperature for one hour.THF was removed and the residue was partitioned between 100 ml EtOAc and100 ml water. The organic layer was washed with water (2×100 ml), driedwith Na₂SO₄ and concentrated. The residue was purified by column(EtOAc/hexane from 25/75 to 100/0 in 45 minutes, 120 g silica). Yield:0.19 g, 68%.

¹H NMR (CDCl₃ 400 MHz): 7.73 (s, 1H), 7.50 (dd, J=8.1, 5.12 Hz, 1H),7.43 (d, J=16.8 Hz, 1H), 7.27 (m, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.13 (s,1H), 7.00 (m, 3H), 6.52 (d, J=16.1 Hz, 1H), 3.90 (s, 3H), 3.71 (m, 1H),3.30 (dd, J=16.1 and 5.9 Hz, 1H), 2.91 (m, 1H), 2.64 (m, 1H), 2.38 (d,J=16.1 Hz, 1H), 2.30 (s, 3H), 2.06, (m, 1H), 1.51 (m, 2H), 1.10 (m, 1H).MS (M+1): 445.2.

Compounds 19-21 in Table 1 were synthesized using methods similar tothat of method B. Starting from2-(tert-butyldimethylsilyloxy)-1-(4-fluorophenyl)ethanone, compounds 16and 17 in Table 1 were synthesized using methods similar to that ofmethod B.

Method C

To a dichloromethane solution of C1 is added 1 eq ofN-chlorosuccinimide, and the solution is stirred until the disappearanceof C1 monitored by a reverse phase HPLC system. To this solution isadded C2 (1 eq) and the solution is stirred overnight to generatecompound C3, which is isolated by methods known to those with ordinaryskill in the art.

Assay:

Secretase Reaction and Aβ Analysis in Whole Cells: HEK293 cellsoverexpressing APP with Swedish and London mutations were treated withthe specified compounds for 5 hour at 37° C. in 100 ml of DMEM mediumcontaining 10% fetal bovine serum. At the end of the incubation, totalAβ, Aβ40 and Aβ42 were measured using electrochemiluminescence (ECL)based sandwich immunoassays. Total Aβ was determined using a pair ofantibodies TAG-W02 and biotin-4G8, Aβ40 was identified with antibodypairs TAG-G2-10 and biotin-4G8, while Aβ42 was identified with TAG-G2-11and biotin-4G8. The ECL signal was measured using Sector Imager 2400(Meso Scale Discovery).

MS Analysis of Aβ Profile: Aβ profile in conditioned media wasdetermined using surface enhanced laser desorption/ionization (SELDI)mass spectrometry. Conditioned media was incubated with antibody W02coated PS20 ProteinChip array. Mass spectra of Aβ captured on the arraywere read on SELDI ProteinChip Reader (Bio-Rad) according tomanufacture's instructions.

CSF Aβ Analysis: Aβ in rat CSF was determined using MSD technology asdescribed above. Aβ40 was measured using antibody pair Tag-G2-10 andbiotin-4G8, while Aβ42 was measured using Tag-anti Aβ42 (Meso ScaleDiscovery) and biotin-4G8. The ECL signal was measured using SectorImager 2400 (Meso Scale Discovery).

Matrix-assisted laser desorption/ionization mass spectrometric (MALDIMS) analysis of Aβ is performed on a Voyager-DE STR mass spectrometer(ABI, Framingham, Mass.). The instrument is equipped with a pulsednitrogen laser (337 nm). Mass spectra are acquired in the linear modewith an acceleration voltage of 20 kV. Each spectrum presented in thiswork represents an average of 256 laser shots. To prepare thesample-matrix solution, 1 μL of immunoprecipitated A□ sample is mixedwith 3 μL of saturated α-cyano-4-hydroxycinnamic acid solution in 0.1%TFA/acetonitrile. The sample-matrix solution is then applied to thesample plate and dried at ambient temperature prior to massspectrometric analysis. All the spectra are externally calibrated with amixture of bovine insulin and ACTH (18-39 clip).

Compounds 1, 2, and 9 to 12 had a Cellular Ab42 IC50 in the range of 200nM to 20,000 nM, with an Ab total to Ab42 selectivity in the range of100 to 6 fold.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A compound, or pharmaceutically acceptable salts, solvates, esters orprodrugs of said compound, said compound having the general structureshown in the formula:

wherein: either (i) R² and R⁶ are joined together to form a C4-C8cycloalkyl, C4-C8 cycloalkenyl, 5-8 membered heterocyclyl or 5-8membered heterocyclenyl moiety, with each of said cycloalkyl orheterocyclyl moiety being unsubstituted or optionally independentlybeing substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below; or (ii) R² and R⁶ are joinedtogether to form a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8 memberedheterocyclyl or 5-8 membered heterocyclenyl moiety, with each of saidcycloalkyl or heterocyclyl moiety being unsubstituted or optionallyindependently being substituted with 1-5 substituents which can be thesame or different, each substituent being independently selected fromthe group consisting of the moieties shown below; and R⁶ and R⁷ arejoined together to form a C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 5-8membered heterocyclyl or 5-8 membered heterocyclenyl moiety, with eachof said cycloalkyl or heterocyclyl moiety being unsubstituted oroptionally independently being substituted with 1-5 substituents whichcan be the same or different, each substituent being independentlyselected from the group consisting of the moieties shown below; and U is

or N; G is O or S; V is selected from the group consisting of a bond, O,—C(O)—, and N(R¹⁴); R¹, R⁵ and R⁷ (when R⁷ is not joined to R⁶) can bethe same or different, each being independently selected from the groupconsisting of H, alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-, wherein each ofsaid alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-,cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl- and heterocyclylalkyl- can be unsubstituted or optionallyindependently substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below; or, alternatively, R¹ and R⁸ aretaken together to form a bond; R¹⁴ is selected from the group consistingof H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶),—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and—P(O)(OR¹⁵)(OR¹⁶); R⁸ is selected from the group consisting of H,alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-,cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl- and heterocyclylalkyl-, with each of said alkyl-, alkenyl-and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- andheterocyclylalkyl- being unsubstituted or optionally independentlysubstituted with 1-3 substituents which can be the same or different,each substituent being independently selected from the group consistingof the moieties shown below; R¹⁰ is selected from the group consistingof a bond, alkyl-, alkenyl- and alkynyl-, aryl-, alkylaryl-,cycloalkyl-, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl-, heterocyclylalkyl- and the moieties:

where X is O, N(R¹⁴) or S; wherein each of said alkyl-, alkenyl- andalkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- heterocyclylalkyl- for R¹⁰as well as the above-noted moieties for R¹⁰ can be unsubstituted oroptionally independently substituted with 1-3 substituents which can bethe same or different, each being independently selected from the groupconsisting of the moieties shown below; and R⁹ is selected from thegroup consisting of alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,alkylaryl-, cycloalkyl-, cycloalkylalkyl-, heteroaryl-,heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl-, wherein each ofsaid alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-,cycloalkyl-, cycloalkytalkyl-, heteroaryl-, heteroarylalkyl-,heterocyclyl- and heterocyclylalkyl-can be unsubstituted or optionallyindependently substituted with 1-3 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below, R¹⁵, R¹⁶ and R¹⁷ areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl,arytheterocyclyl, R¹⁸-alkyl, R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl,R¹⁸-heterocyclyl, R¹⁸-heterocyclylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl,R¹⁸-heteroaryl and R¹⁸-heteroarylalkyl; R¹⁸ is 1-5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂, halo,heteroaryl, HO-alkyoxyalkyl, —CF₃, —ON, alkyl-CN, —C(O)R¹⁰, —C(O)OH,—C(O)OR¹⁰, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl,—O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); or, alternately, two R¹⁸ moieties onadjacent carbons can be linked together to form:

R¹⁰ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl; R²⁰ isalkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl orheteroarylalkyl; wherein each of the alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R¹, R²—R⁶, R⁵, R⁷, R⁸,R⁹, R¹⁰ and R¹⁴ is independently unsubstituted or optionally substitutedby 1 to 5 R²¹ groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁸),—SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁸), —N(R¹⁶)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶),—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, N(R¹⁵)S(O)₂R¹⁶,—CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶,—CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; andwherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl.heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R²¹ is independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵.
 2. A compound, or pharmaceuticallyacceptable salts, solvates, esters or prodrugs of said compound, saidcompound having the general structure shown in the formula;

wherein: U is

or N; G is O or S; V is selected from the group consisting of a bond, O,—C(O), and N(R¹⁹); R¹, R⁵ and A⁷ can be the same or different, eachbeing independently selected from the group consisting of H, alkyl-,alkenyl- and alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-, heterocyclyl- andheterocyclylalkyl-, wherein each of said alkyl-, alkenyl- and alkynyl-,aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkylalkyl-,heteroaryl-, heteroarylalkyl-, heterocyclyl- and heterocyclylalkyl- canbe unsubstituted or optionally independently substituted with 1-5substituents which can be the same or different, each substituent beingindependently selected from the group consisting of the moieties shownbelow; R² and R⁶ are joined together to form a C4-C8 cycloalkyl or a 5-8membered heterocyclyl moiety, with each of said cycloalkyl orheterocyclyl moiety being unsubstituted or optionally independentlybeing substituted with 1-5 substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of the moieties shown below; R¹⁴ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶),—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and—P(O)(OR¹⁵)(OR¹⁶); R⁸ is selected from the group consisting of H, alkyl,cycloalkyl, aryl and heteroaryl, with each of said alkyl, cycloalkyl,aryl and heteroaryl being unsubstituted or optionally independentlysubstituted with 1-3 substituents which can be the same or different,each substituent being independently selected from the group consistingof halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxygroups; R¹⁰ is selected from the group consisting of a bond, aryl,heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, alkylaryl,heteroarylalkyl, heterocyclylalkyl and the moieties:

where X is O, NH or S; wherein each of said aryl, heteroaryl,cycloalkyl, heterocyclyl and the above-noted moieties for R¹⁰ can beunsubstituted or optionally independently substituted with 1-3substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups: and R⁹ isselected from the group consisting of alkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl andheterocyclylalkyl wherein each of said alkyl, aryl, heteroaryl andheterocyclyl can be unsubstituted or optionally independentlysubstituted with 1-3 substituents which can be the same or different,each substituent being independently selected from the group consistingof halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxygroups.
 3. The compound of claim 1, wherein U is C(R⁵).
 4. The compoundof claim 1, wherein U is N,
 5. The compound of claim 1, wherein G is O.6. The compound of claim 1, wherein G is S.
 7. The compound of claim 1,wherein R¹ is H; or R¹ is methyl.
 8. The compound of claim 1, wherein R¹is alkyl.
 9. (canceled)
 10. The compound of claim 1, wherein: (a) R² andR⁶ are joined together to form a cyclopentyl ring; or (b) R² and R⁶ arejoined together to form a cyclopentyl ring, which is substituted with1-3 substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups; or (c) R² andR⁶ are joined together to form a cyclohexyl ring; or (d) R² and R⁶ arejoined together to form a cyclohexyl ring, which is substituted with 1-3substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.
 11. Thecompound of claim 1 wherein: (a) R² and R⁶ are joined together to form aring optionally substituted with 1 to 5 independently selected R²¹substitutents, and said ring is fused with an aryl or heteroaryl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents; or (b) R² and R⁶ are joinedtogether to form a ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with an aryl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents; or (c) R² and R⁶ are joinedtogether to form a ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with a phenyl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents; or (d) R² and R⁶ are joinedtogether to form a ring, and said ring is fused with an aryl orheteroaryl ring; or (e) R² and R⁶ are joined together to form a ring,and said ring is fused with a phenyl ring; or (f) R² and R⁶ are joinedtogether to form a heterocyclyl ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and said ring is fused with anaryl or heteroaryl ring, and said resulting fused ring is optionallysubstituted with 1 to 5 independently selected R²¹ substitutents; or (g)R² and R⁶ are joined together to form a heterocyclyl ring optionallysubstituted with 1 to 5 independently selected R²¹ substitutents, andsaid ring is fused with an aryl ring, and said resulting fused ring isoptionally substituted with 1 to 5 independently selected R²¹substitutents; or (h) R² and R⁶ are joined together to form aheterocyclyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with a phenyl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents; or (i) R² and R⁶ are joinedtogether to form a heterocyclyl ring, and said ring is fused with anaryl or heteroaryl ring; or (j) R² and R⁶ are joined together to form aheterocyclyl ring, and said fused with a phenyl ring; or (k) U is N, andR² and R⁶ are joined together to form a piperidinyl ring optionallysubstituted with 1 to 5 independently selected R²⁻¹ substitutents, andsaid ring is fused with an aryl or heteroaryl ring, and said resultingfused ring is optionally substituted with 1 to 5 independently selectedR²¹ substitutents; or (l) U is N, and R² and R⁶ are joined together toform a piperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and said ring is fused with an aryl ring,and said resulting fused ring is optionally substituted with 1 to 5independently selected R²¹ substitutents; or (m) U is N, and R² and R⁶are joined together to form a piperidinyl ring optionally substitutedwith 1 to 5 independently selected R²¹ substitutents, and said ring isfused with a phenyl ring, and said resulting fused ring is optionallysubstituted with 1 to 5 independently selected R²¹ substitutents; or (n)U is N, and R² and R⁶ are joined together to form a piperidinyl ring,and said ring is fused with an aryl or heteroaryl ring; or (o) U is n,and R² and R⁶ are joined together to form a piperidinyl ring (e.g., U isN), and said ring is fused with a phenyl ring.
 12. The compound of claim1 wherein: (a) R² and R⁶ are joined together to form a ring optionallysubstituted with 1 to 5 independently selected R²¹ substitutents, and R⁶and R⁷ are joined together to form a ring optionally substituted with 1to 5 independently selected R²¹ substitutents; or (b) R² and R⁶ arejoined together to form a ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a ring that is fused with an aryl or heteroaryl ring,said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents, (c) R² and R⁶ are joinedtogether to form a ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with an aryl or heteroaryl ring,said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents; or (d) R² and R⁶ are joinedtogether to form a ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form aC4-C8 cycloalkyl ring that is fused with an aryl rind, said resultingfused ring optionally substituted with 1 to 5 independently selected R²¹substitutents; or (e) R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-08cycloalkyl ring that is fused with a phenyl ring, said resulting fusedring optionally substituted with 1 to 5 independently selected R²¹substitutents; or (f) R² and R⁶ are joined together to form a ringoptionally substituted with 1 to 5 independently selected R²¹substitutents, and R⁶ and R⁷ are joined together to form a C4-C8cycloalkyl ring that is fused with a phenyl ring, said phenyl moietybeing substituted with 1-3 independently selected halos; or (g) R² andR⁶ are joined together to form a ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a cyclopentyl ring that is fused with a phenyl ring,said phenyl moiety being substituted with 1-3 F; or (h) R² and R⁶ arejoined together to form a ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a tetrahydopyranyl ring that is fused with a phenylring, said phenyl moiety being substituted with 1-3 F; or (i) R² and R⁶are joined together to form a ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a cyclopentyl ring that is fused with a phenyl ring,wherein said phenyl moiety is substituted with 1 F; or (j) R² and R⁶ arejoined together to form a ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a tetrahydopyranyl ring that is fused with a phenylring, wherein said phenyl moiety is substituted with 1 F; or (k) R² andR⁶ are joined together to form a heterocyclyl ring optionallysubstituted with 1 to 5 independently selected R²¹ substitutents, and R⁶and R⁷ are joined together to form a ring optionally substituted with 1to 5 independently selected R²¹ substitutents; or (l) R² and R⁶ arejoined together to form a heterocyciyl ring optionally substituted with1 to 5 independently selected R²¹ substitutents, and R⁶ and R⁷ arejoined together to form a ring that is fused with an aryl or heteroarylring, said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents; or (m) R² and R⁶ are joinedtogether to form a heterocyclyl ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a C4-C8 cycloalkyl ring that is fused with an aryl orheteroaryl ring, said resulting fused ring optionally substituted with 1to 5 independently selected R²¹ substitutents; or (n) R² and R⁶ arejoined together to form a heterocyclyl ring optionally substituted with1 to 5 independently selected R²¹ substitutents, and R⁶ and R⁷ arejoined together to form a C4-C8 cycloalkyl ring that is fused with anaryl ring, said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents; or (o) R² and R⁶ are joinedtogether to form a heterocyclyl ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a C4-C8 cycloalkyl ring that is fused with a phenylring, said resulting fused ring optionally substituted with 1 to 5independently selected R²¹ substitutents; or (p) R² and R⁶ are joinedtogether to form a heterocyclyl ring optionally substituted with 1 to 5independently selected R²¹ substitutents, and R⁶ and R⁷ are joinedtogether to form a C4-C8 cycloalkyl ring that is fused with a phenylring, said phenyl moiety being substituted with 1-3 independentlyselected halos; or (q) R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, said phenyl moietybeing substituted with 1-3 independently selected halos; or (r) R² andR⁶ are joined together to form a piperidinyl ring optionally substitutedwith 1 to 5 independently selected R²¹ substitutents, and R^(b) and R⁷are joined together to form a tetrahydopyranyl ring that is fused with aphenyl ring, said phenyl moiety being substituted with 1-3 independentlyselected halos; or (s) R² and R⁶ are joined together to form apiperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form acyclopentyl ring that is fused with a phenyl ring, wherein said phenylmoiety is substituted with 1 F; or (t) R² and R⁶ are joined together toform a piperidinyl ring optionally substituted with 1 to 5 independentlyselected R²¹ substitutents, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, wherein saidphenyl moiety is substituted with 1 F; or (u) R² and R⁶ are joinedtogether to form a heterocyclyl ring, and R⁶ and R⁷ are joined togetherto form a C4-C8 cycloalkyl ring that is fused with a phenyl ring, saidphenyl moiety being substituted with 1-3 independently selected halos;or (v) R² and R⁶ are joined together to form a piperidinyl ring, and R⁶and R⁷ are joined together to form a cyclopentyl ring that is fused witha phenyl ring, said phenyl moiety being substituted with 1-3independently selected halos; or (w) R² and R⁶ are joined together toform a piperidinyl ring, and R⁶ and R⁷ are joined together to form atetrahydopyranyl ring that is fused with a phenyl ring, said phenylmoiety being substituted with 1-3 independently selected halos; or (x)R² and R⁶ are joined together to form a piperidinyl ring, and R⁶ and R⁷are joined together to form a cyclopentyl ring that is fused with aphenyl ring, wherein said phenyl moiety is substituted with 1 F; or (y)R² and R⁶ are joined together to form a piperidinyl ring, and 19⁶ and R⁷are joined together to form a tetrahydopyranyl ring that is fused with aphenyl ring, wherein said phenyl moiety is substituted with 1 F.
 13. Thecompound of claim 1, wherein: (a) U is N, G is O, and R² and R⁶ arejoined together to form a piperidinyl ring including the N of U as thenitrogen of said piperidinyl ring, which is unsubstituted; or (b) U isN, G is O, and R² and R⁶ are joined together to form a piperidinyl ringincluding the N of U as the nitrogen of said piperidinyl ring, whereinsaid piperidinyl ring is substituted with 1-3 substituents which can bethe same or different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxyand alkoxy groups; or (c) U is N, G is O, and R² and R⁶ are joinedtogether to form a pyrrolidinyl ring including the N of U as thenitrogen of said pyrrolidinyl ring, which is unsubstituted; or (d) U isN, G is O, and R² and R⁵ are joined together to form a pyrrolidinyl ringincluding the N of U as the nitrogen of said pyrrolidinyl ring, whereinsaid pyrrolidinyl ring is substituted with 1-3 substituents which can bethe same or different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxyand alkoxy groups; or (e) U is N, G is O, and R² and R⁶ are joinedtogether to form a piperazinyl ring including the N of U as a nitrogenof said piperazinyl ring, which is unsubstituted; or (f) U is N, G is O,and R² and R⁶ are joined together to form a piperazinyl ring includingthe N of U as a nitrogen of said piperazinyl ring, wherein saidpiperazinyl ring is substituted with 1-3 substituents which can be thesame or different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxyand alkoxy groups.
 14. The compound of claim 1, wherein (a) R² and R⁶are joined together to form a morpholinyl ring which is unsubstituted;or (b) R² and R⁶ are joined together to form a morpholinyl ring, whichis substituted with 1-3 substituents which can be the same or different,each being independently selected from the group consisting of halo,alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups; or(c) R² and R⁶ are joined together to form a pyranyl ring which isunsubstituted; or (d) R² and R⁶ are joined together to form a pyranylring, which is substituted with 1-3 substituents which can be the sameor different, each being independently selected from the groupconsisting of halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxyand alkoxy groups; or (e) R² and R⁶ are joined together to form apyrrolidinyl ring which is unsubstituted; or (f) R² and R⁶ are joinedtogether to form a pyrrolidinyl ring, which is substituted with 1-3substituents which can be the same or different, each beingindependently selected from the group consisting of halo, alkyl, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxy groups.
 15. Thecompound of claim 1, wherein R⁷ is aryl.
 16. The compound of claim 1,wherein R⁷ is an unsubstituted phenyl; or R⁷ is a phenyl which issubstituted with 1-4 substituents which can be the same or different,each substituent being independently selected from the group consistingof halo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryland heteroaryl groups; or R⁷ is 4-fluorophenyl or R⁷ is unsubstitutednaphthyl; or R⁷ is naphthyl which is substituted with 1-4 substituentswhich can be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, —CN, —NH₂,—NH(alkyl), —N(alkyl)₂, hydroxy, alkoxy, aryl and heteroaryl groups; orR⁷ is unsubstituted biphenyl; or R⁷ is biphenyl which is substitutedwith 1-4 substituents which can be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, hydroxy and alkoxygroups; or R⁷ is 3-(1,1′-biphenyl)-yl; or R⁷ is 4-(1,1′-biphenyl)-yl.17. (canceled)
 18. (canceled)
 19. (canceled)
 20. The compound of claim1, wherein R⁸ is H; or R⁸ is methyl.
 21. The compound of claim 1,wherein R⁸ is alkyl.
 22. (canceled)
 23. The compound of claim 1, whereinR¹⁰ is aryl; or R¹⁰ is heteroaryl.
 24. The compound of claim 1, whereinR¹⁰ is phenyl.
 25. (canceled)
 26. The compound of claim 1, wherein R⁹ isunsubstituted heteroaryl; or R⁹ is heteroaryl which is substituted with1-3 substituents which can be the same or different, each substituentbeing independently selected from the group consisting of halo, alkyl,CN, NH₂, NH(alkyl), N(alkyl)₂, hydroxyl, alkoxy, alkyl substituted withhalo, and alkyl substituted with —OR¹⁵.
 27. (canceled)
 28. The compoundof claim 1, wherein R⁹ is imidazol-1-yl; or R⁹ is4-methyl-imidazol-1-yl; or R⁹ is 5-chloro-4-methyl-imidazol-1-yl.29.-30. (canceled)
 31. A compound, or pharmaceutically acceptable salts,solvates, esters or prodrugs of said compound, said compound having thegeneral structure shown in the formula:

wherein (1) U is C(H) or (C(alkyl); R¹ is H; R² and R⁶ are connected toform a 4-7 membered cycloalkyl ring; R⁷ is phenyl; R⁸ is H; R¹⁰ isalkoxy-substituted phenyl; and R⁹ is 4-methyl-imidazol-1-yl; or (2) U isCH, C(alkyl) or N; R¹ is H; R² and R⁶ are connected to form a 5-7membered heterocyclyl ring: R⁷ is phenyl; R⁸ is H; R¹⁰ isalkoxy-substituted phenyl; and R⁹ is 4-methyl-imidazol-1-yl; or (3) U isCH, C(alkyl) or N; R¹ is H; R² and R⁶ are connected to form apiperidinyl ring; R⁷ is 4-fluoro-phen-1-yl; R⁸ is H; R¹⁰ is phenyl; andR⁹ is imidazol-1-yl; or (4) U is CH, C(alkyl) or N; R¹ is H; R² and R⁶are connected to form a piperazinyl ring; R⁷ is 4-fluoro-phen-1-yl; R⁸is H: R¹⁰ is phenyl; and R⁹ is 5-chloro-4-methyl-imidazol-1-yl; or (5) Uis CH, C(alkyl) or N; R¹ is H; R² and R⁶ are connected to form apiperidinyl ring; R⁷ is phenyl R⁸ is H; R¹⁰ is phenyl; and R⁹ isimidazol-1-yl: or (6) U is CH, C(alkyl) or N; R¹ is H; R⁷ is H; R² andR⁶ are connected to form a piperazinyl ring; R⁸ is H; R¹⁰ isalkoxy-substituted phenyl; and R⁹ is imidazol-1-yl; or (7) U is CH,C(alkyl) or N; R¹ is H; R⁷ is (alkoxy)aryl-alkyl-; R² and R⁶ areconnected to form a piperidinyl ring: R⁸ is H; R¹⁰ is(alkoxy-substituted)aryl; and R⁹ is imidazol-1-yl; or (8) U is CH,C(alkyl) or N; R¹ is H; R² and R⁶ are connected to form a piperazinylring; R⁷ is substituted with halo; R⁸ H: R¹⁰ is(alkoxy-substituted)aryl; and R⁹ is imidazol-1-yl. 32.-38. (canceled)39. The compound of claim 1 selected from the group consisting of thecompounds of formulas 1A to 40A, or a pharmaceutically acceptable salt,solvate or ester thereof.
 40. (canceled)
 41. A compound selected fromthe group consisting of the compounds of formulas: 1 to 7 and 9 to 22,or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof.
 42. A compound selected from the group consisting of thecompounds of formulas: 1 to 7 and 9 to
 22. 43. The compound of claim 42wherein said compound is a pharmaceutically acceptable salt of thecompound of claim 42; or said compound is a solvate of the compound ofclaim 42; or said compound is an ester of the compound of claim 42.44.-45. (canceled)
 46. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1, and apharmaceutically acceptable carrier.
 47. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 42,and a pharmaceutically acceptable carrier. 48.-50. (canceled)
 51. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 42, and a pharmaceutically acceptable carrier,and an effective amount of one or more BACE inhibitors.
 52. Apharmaceutical composition: (1) comprising a therapeutically effectiveamount of at least one compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, or ester thereof, and at least onepharmaceutically acceptable carrier, or (2) comprising a therapeuticallyeffective amount of at least one compound of claim 1, or apharmaceutically acceptable salt, solvate, or ester thereof, and atleast one pharmaceutically acceptable carrier, and an effective amountof one or more other pharmaceutically active drugs selected form thegroup consisting of: (a) drugs useful for the treatment of Alzheimer'sdisease, (b) drugs useful for inhibiting the deposition of amyloidprotein (e.g., amyloid beta protein) in, on or around neurologicaltissue, (c) drugs useful for treating neurodegenerative diseases, and(d) drugs useful for inhibiting gamma-secretase, or (3) comprising atherapeutically effective amount of at least one compound of claim 1, ora pharmaceutically acceptable salt, solvate, or ester thereof, and atleast one pharmaceutically acceptable carrier, and an effective amountof one or more BACE inhibitors, (4) comprising a therapeuticallyeffective amount of at least one compound of claim 1, or apharmaceutically acceptable salt, solvate, or ester thereof, and atleast one pharmaceutically acceptable carrier, and effective amount ofone or more cholinesterase inhibitors, or (5) comprising atherapeutically effective amount of at least one compound of claim 1,and at least one pharmaceutically acceptable carrier, and effectiveamount of one or more cholinesterase inhibitors, or (6) comprising atherapeutically effective amount of at least one compound of claim 1, ora pharmaceutically acceptable salt, solvate, or ester thereof, and atleast one pharmaceutically acceptable carrier, and effective amount ofone or more BACE inhibitors, muscarinic antagonists, cholinesteraseinhibitors; gamma secretase inhibitors; gamma secretase modulators;HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents;N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies;vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptorinverse agonists or CB1 receptor antagonists; an antibiotic; growthhormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4inhibitors: GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors and cholesterol absorptioninhibitors, or (7) comprising a therapeutically effective amount of atleast one compound of claim 1, and at least one pharmaceuticallyacceptable carrier, and effective amount of one or more BACE inhibitors,muscarinic antagonists, cholinesterase inhibitors; gamma secretaseinhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors;non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptorantagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; an antibiotic; growth hormone secretagogues; histamine H3antagonists; AMPA agonists; PDE4 inhibitors; GABA_(A) inverse agonists;inhibitors of amyloid aggregation; glycogen synthase kinase betainhibitors; promoters of alpha secretase activity; PDE-10 inhibitors andcholesterol absorption inhibitors, or (8) comprising a therapeuticallyeffective amount of at least one compound of claim 1, or apharmaceutically acceptable salt, solvate, or ester thereof, and atleast one pharmaceutically acceptable carrier, and an effective amountof donepezil hydrochloride, or (9) comprising a therapeuticallyeffective amount of at least one compound of claim 1, and at least onepharmaceutically acceptable carrier, and an effective amount ofdonepezil hydrochloride. 53.-57. (canceled)
 58. A method of treatingAlzheimer's disease, comprising administering an effective amount of acompound of claim 1 to a patient in need of treatment.
 59. A method oftreating Alzheimer's disease, comprising administering an effectiveamount of a compound of claim 42 to a patient in need of treatment. 60.A method of (a) modulating gamma-secretase, (b) treating one or moreneurodegenerative diseases, (c) inhibiting the deposition of amyloidprotein in, on or around neurological tissue, or (d) treatingAlzheimer's disease, comprising administering administering: (1) one ormore compounds of claim 1; or (2) (a) an effective amount of a compoundof claim 1, and (b) an effective amount of one or more otherpharmaceutically active ingredients selected from the group consistingof: BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors;gamma secretase inhibitors; gamma secretase modulators; HMG-CoAreductase inhibitors; non-steroidal anti-inflammatory agents;N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies;vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptorinverse agonists or CB1 receptor antagonists; an antibiotic; growthhormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors and cholesterol absorptioninhibitors, to a patient in need of such treatment.
 61. A method oftreating Alzheimer's disease, comprising administering an effectiveamount of a compound of claim 1, and an effective amount of one or morecompounds selected from the group consisting of Aβ antibody inhibitors,gamma secretase inhibitors and beta secretase inhibitors, to a patientin need of such treatment.
 62. A method of treating Alzheimer's disease,comprising administering an effective amount of a compound of claim 1,and an effective amount of one or more BACE inhibitors, to a patient inneed of such treatment,
 63. A method of: (1) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount of one ormore cholinesterase inhibitors, to a patient in need of treatment, or(2) treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, in combination with aneffective amount of donepezil hydrochloride, to a patient in need oftreatment, or (3) treating Alzheimer's disease, comprising administeringan effective amount of a compound claim 1, in combination with aneffective amount of one or more cholinesterase, to a patient in need oftreatment, or (4) treating Alzheimer's disease, comprising administeringan effective amount of a compound of claim 1, in combination with aneffective amount of donepezil hydrochloride, to a patient in need oftreatment, or (5) treating Alzheimer's disease, comprising administeringan effective amount of one or more compounds of claim 1, in combinationwith an effective amount of (rivastigmine, to a patient in need of suchtreatment, or (6) treating Alzheimer's disease, comprising administeringan effective amount of one or more compounds of claim 1, in combinationwith an effective amount of tacrine, to a patient in need of suchtreatment, or (7) treating Alzheimer's disease, comprising administeringan effective amount of one or more compounds of claim 1, in combinationwith an effective amount of a Tau kinase inhibitor, to a patient in needof such treatment, or (8) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more Tau kinaseinhibitors selected from the group consisting of: GSK3beta inhibitors,cdk5 inhibitors, ERK inhibitors, to a patient in need of such treatment,or (9) treating Alzheimer's disease, comprising administering aneffective amount of one or more compounds of claim 1, in combinationwith an effective amount of one anti-Abeta vaccination, to a patient inneed of such treatment, or (10) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more APP ligands, to apatient in need of such treatment, or (11) treating Alzheimer's disease,comprising administering an effective amount of one or more compounds ofclaim 1, in combination with an effective amount of one or more agentsthat upregulate insulin degrading enzyme and/or neprilysin, to a patientin need of such treatment, or (12) treating Alzheimer's disease,comprising administering an effective amount of one or more compounds ofclaim 1, in combination with an effective amount of one or morecholesterol lowering agents, to a patient in need of such treatment, or(13) treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, in combination with aneffective amount of one or more cholesterol lowering agents selectedfrom the group consisting of: Atorvastatin, Fluvastatin, Lovastatin,Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, andEzetimibe, to a patient in need of such treatment, or (14) treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of claim 1, in combination with an effective amount ofone or more fibrates, to a patient in need of such treatment, or (15)treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, in combination with aneffective amount of one or more fibrates selected from the groupconsisting of, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate,to a patient in need of such treatment, or (16) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount of one ormore LXR agonists, to a patient in need of such treatment, or (17)treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, in combination with aneffective amount of one or more LRP mimics, to a patient in need of suchtreatment, or (18) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more 5-HT6 receptorantagonists, to a patient in need of such treatment, or (19) treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of claim 1, in combination with an effective amount ofone or more nicotinic receptor agonists, to a patient in need of suchtreatment, or (20) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more H3 receptorantagonists, to a patient in need of such treatment, or (21) treatingAlzheimer's disease, comprising administering an effective amount of oneor more compounds of claim 1, in combination with an effective amount ofone or more histone deacetylase inhibitors, to a patient in need of suchtreatment, or (22) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more hsp90 inhibitors,to a patient in need of such treatment, or (23) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount of one ormore m1 muscarinic receptor agonists, to a patient in need of suchtreatment, or (24) treating Alzheimer's disease, comprisingadministering an effective amount of one or more compounds of claim 1,in combination with an effective amount of one or more 5-HT6 receptorantagonists mGluR1 or mGluR5 positive allosteric modulators or agonists,to a patient in need of such treatment, or (25) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount of one ormore mGluR2/3 antagonists, to a patient in need of such treatment, or(26) treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of formula I, in combination with aneffective amount of one or more anti-inflammatory agents that can reduceneuroinflammation, to a patient in need of such treatment, or (27)treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, it combination with aneffective amount of one or more Prostaglandin EP2 receptor antagonists,to a patient in need of such treatment, or (28) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount of one ormore PAI-1 inhibitors, to a patient in need of such treatment, or (29)treating Alzheimer's disease, comprising administering an effectiveamount of one or more compounds of claim 1, in combination with aneffective amount of one or more agents that can induce Abeta efflux, toa patient in need of such treatment, or (30) treating Alzheimer'sdisease, comprising administering an effective amount of one or morecompounds of claim 1, in combination with an effective amount ofgelsolin, to a patient in need of such treatment, or (31) treating Downssyndrome, comprising administering an effective amount of one or morecompounds of claim 1 to a patient in need of treatment, or (32) treatingDowns syndrome, comprising administering an effective amount of acompound of claim 1 to a patient in need of treatment, or (33) treatingDowns syndrome, comprising administering an effective amount of one ormore compounds of claim 1, in combination with an effective amount ofone or more cholinesterase inhibitors, to a patient in need oftreatment. (34) treating Downs syndrome, comprising administering aneffective amount of one or more compounds of claim 1, in combinationwith an effective amount of donepezil hydrochloride, to a patient inneed of treatment, or (35) treating Downs syndrome, comprisingadministering an effective amount of a compound of claim 1, incombination with an effective amount of one or more cholinesteraseinhibitors, to a patient in need of treatment. (36) treating Downssyndrome, comprising administering an effective amount of a compound ofclaim 1, in combination with an effective amount of donepezilhydrochloride, to a patient in need of treatment, or (37) treating mildcognitive impairment, comprising administering an effective amount ofone or more compounds of claim 1 to a patient in need of treatment, or(38) treating glaucoma, comprising administering an effective amount ofone or more compounds of claim 1 to a patient in need of treatment, or(39) treating cerebral amyloid angiopathy, comprising administering aneffective amount of one or more compounds of claim 1 to a patient inneed of treatment, or (40) treating stroke, comprising administering aneffective amount of one or more compounds of claim 1 to a patient inneed of treatment, or (41) This invention also provides a method oftreating dementia, comprising administering an effective amount of oneor more compounds of claim 1 to a patient in need of treatment, or (42)treating microgliosis, comprising administering an effective amount ofone or more compounds of claim 1 to a patient in need of treatment, or(43) treating brain inflammation, comprising administering an effectiveamount of one or more compounds of claim 1 to a patient in need oftreatment, or (44) treating olfactory function loss, comprisingadministering an effective amount of one or more compounds of claim 1 toa patient in need of treatment.
 64. A kit comprising, in separatecontainers, in a single package, pharmaceutical compositions for use incombination, wherein one container comprises an effective amount of acompound of claim 1 in a pharmaceutically acceptable carrier, andanother container comprises an effective amount of anotherpharmaceutically active ingredient, the combined quantities of thecompound of claim 1 and the other pharmaceutically active ingredientbeing effective to: (a) treat Alzheimer's disease, or (b) inhibit thedeposition of amyloid protein in, on or around neurological tissue, or(c) treat neurodegenerative diseases, or (d) modulate the activity ofgamma-secretase.